Anti-hiv compounds

ABSTRACT

This invention provides, among other things, tetrahydroisoquinolines useful for treating viral infections, pharmaceutical formulations containing such compounds, as well as methods of inhibiting the replication of a virus, such as HIV, or treating a disease, such as AIDS.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/092,115, filed Dec. 15, 2014, which is incorporatedby reference in its entirety for all purpose.

BACKGROUND OF THE INVENTION

There is a need in the art to discover new compounds useful asantivirals.

It has now been discovered that certain tetrahydroisoquinolines aresurprisingly effective antivirals. This, and other uses of thesecompounds are described herein.

SUMMARY OF THE INVENTION

This invention provides, among other things, novel compounds useful fortreating viral infections, pharmaceutical formulations containing suchcompounds, as well as methods of inhibiting the replication of a virusor treating a disease.

In an exemplary embodiment, the invention provides a compound of theformula which is:

in which

-   -   R¹ is H or unsubstituted alkoxy or phenyl substituted alkoxy,    -   R² is H or CF₃ or unsubstituted alkoxy or phenyl substituted        alkoxy,    -   R³ is H or —C(O)OR⁴ or —C(O)R⁴ or —C(O)NR⁴R⁵, wherein        -   R⁴ and R⁵ are independently selected from unsubstituted            alkyl, unsubstituted phenyl, or unsubstituted pyridinyl;    -   A is substituted or unsubstituted phenyl.        Also provided are hydrates, salts and solvates of these        compounds.

In an exemplary embodiment, there is provided a pharmaceuticalformulation comprising a compound of the invention and apharmaceutically acceptable diluent or carrier.

Also provided is a method of treating a subject infected with alentivirus, e.g., human immunodeficiency virus (HIV). The methodcomprises, administering to the subject a therapeutically effectiveamount of a compound of the invention.

Other embodiments, objects and advantages of the invention are apparentfrom the detailed description that follows.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Abbreviations

As used herein, the singular forms “a,” “an”, and “the” include pluralreferences unless the context clearly dictates otherwise. For example,reference to “an active agent” includes a single active agent as well astwo or more different active agents in combination. It is to beunderstood that present teaching is not limited to the specific dosageforms, carriers, or the like, disclosed herein and as such may vary.

The abbreviations used herein generally have their conventional meaningwithin the chemical and biological arts.

The following abbreviations have been used: Ac is acetyl; AcOH is aceticacid; ACTBr is cetyltrimethylammonium bromide; AIBN isazobisisobutyronitrile or 2,2 azobisisobutyronitrile; aq. is aqueous; Aris aryl; B₂pin₂ is bis(pinacolato)diboron; Bn is, in general, benzyl[see Cbz for one example of an exception]; (BnS)₂ is benzyl disulfide;BnSH is benzyl thiol or benzyl mercaptan; BnBr is benzyl bromide; Boc istert-butoxy carbonyl; Boc₂O is di-tert-butyl dicarbonate; Bz is, ingeneral, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z isbenzyloxycarbonyl or carboxybenzyl; Cs₂CO₃ is cesium carbonate; CSA iscamphor sulfonic acid; CTAB is cetyltrimethylammonium bromide; Cy iscyclohexyl; DABCO is 1,4-diazabicyclo[2.2.2]octane; DCM isdichloromethane or methylene chloride; DHP is dihydropyran; DIAD isdiisopropyl azodicarboxylate; DIEA or DIPEA isN,N-diisopropylethylamine; DMAP is 4-(dimethylamino)pyridine; DME is1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO isdimethylsulfoxide; equiv or eq. is equivalent; EtOAc is ethyl acetate;EtOH is ethanol; Et₂O is diethyl ether; EDCI isN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; ELS isevaporative light scattering; equiv or eq is equivalent; h is hours;HATU is 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HOBt is N-hydroxybenzotriazole; HCl is hydrochloricacid; HPLC is high pressure liquid chromatography; ISCO Companion isautomated flash chromatography equipment with fraction analysis by UVabsorption available from Presearch; KOAc or AcOK is potassium acetate;K₂CO₃ is potassium carbonate; LiAlH₄ or LAH is lithium aluminum hydride;LDA is lithium diisopropylamide; LHMDS is lithium bis(trimethylsilyl)amide; KHMDS is potassium bis(trimethylsilyl) amide; LiOH is lithiumhydroxide; m-CPBA is 3-chloroperoxybenzoic acid; MeCN or ACN is methylcyanide or cyanomethane or ethanenitrile or acetonitrile which are allnames for the same compound; MeOH is methanol; MgSO₄ is magnesiumsulfate; mins or min is minutes; Mp or MP is melting point; NaCNBH₃ issodium cyanoborohydride; NaOH is sodium hydroxide; Na₂SO₄ is sodiumsulfate; NBS is N-bromosuccinimide; NH₄Cl is ammonium chloride; NIS isN-iodosuccinimide; N₂ is nitrogen; NMM is N-methylmorpholine; n-BuLi isn-butyllithium; overnight is 0/N; PdCl₂(pddf) is1,1′-Bis(diphenylphosphino) ferroceneldichloropalladium(II); Pd/C is thecatalyst known as palladium on carbon; Pd₂(dba)₃ is an organometalliccatalyst known as tris(dibenzylideneacetone) dipalladium(0); Ra Ni orRaney Ni is Raney nickel; Ph is phenyl; PMB is p-methoxybenzyl; PrOH is1-propanol; iPrOH is 2-propanol; POCl₃ is phosphorus chloride oxide;PTSA is para-toluene sulfonic acid; Pyr. or Pyr or Py as used hereinmeans Pyridine; RT or rt or r.t. is room temperature; sat. is saturated;Si-amine or Si—NH₂ is amino-functionalized silica, available fromSiliCycle; Si-pyr is pyridyl-functionalized silica, available fromSiliCycle; TEA or Et₃N is triethylamine; TFA is trifluoroacetic acid;Tf₂O is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran; TFAAis trifluoroacetic anhydride; THP is tetrahydropyranyl; TMSI istrimethylsilyl iodide; H₂O is water; diNO₂PhSO₂Cl is dinitrophenylsulfonyl chloride; 3-F-4-NO₂-PhSO₂Cl is 3-fluoro-4-nitrophenylsulfonylchloride; 2-MeO-4-NO₂-PhSO₂Cl is 2-methoxy-4-nitrophenylsulfonylchloride; and (EtO)₂POCH₂COOEt is a triethylester of phosphonoaceticacid known as triethyl phosphonoacetate.

“Compound of the invention,” as used herein refers to the compoundsdiscussed herein, salts (e.g. pharmaceutically acceptable salts),prodrugs, solvates and hydrates of these compounds.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents, which would result from writing thestructure from right to left, e.g., —CH₂O— is intended to also recite—OCH₂—.

The term “poly” as used herein means at least 2. For example, apolyvalent metal ion is a metal ion having a valency of at least 2.

“Moiety” refers to a radical of a molecule that is attached to theremainder of the molecule.

The symbol

, whether utilized as a bond or displayed perpendicular to a bond,indicates the point at which the displayed moiety is attached to theremainder of the molecule.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). In some embodiments, the term “alkyl” means astraight or branched chain, or combinations thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals. Examples of saturated hydrocarbon radicals include, but arenot limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers.

The term “alkenylene” by itself or as part of another substituent meansa divalent radical derived from an alkene.

The term “cycloalkylene” by itself or as part of another substituentmeans a divalent radical derived from a cycloalkane.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from an heteroalkane.

The term “heterocycloalkylene” by itself or as part of anothersubstituent means a divalent radical derived from an heterocycloalkane.

The term “arylene” by itself or as part of another substituent means adivalent radical derived from an aryl.

The term “heteroarylene” by itself or as part of another substituentmeans a divalent radical derived from heteroaryl.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom. In someembodiments, the term “heteroalkyl,” by itself or in combination withanother term, means a stable straight or branched chain, or combinationsthereof, consisting of the stated number of carbon atoms and at leastone heteroatom. In an exemplary embodiment, the heteroatoms can beselected from the group consisting of O, N and S, and wherein thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) O, N and Smay be placed at any interior position of the heteroalkyl group or atthe position at which the alkyl group is attached to the remainder ofthe molecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃. Similarly, the term “heteroalkylene” byitself or as part of another substituent means a divalent radicalderived from heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and R′ C(O)₂—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 or 2 or 3 rings), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms. In an exemplary embodiment, theheteroatom is selected from B, N, O, and S, wherein the nitrogen andsulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. A heteroaryl group can be attached to theremainder of the molecule through a heteroatom. Non-limiting examples ofaryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR′″″—C(NR′R″R′″)═NR″″, —NR″″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR″SO₂R′, —CN, —NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R′, R″, R′″, R″″and R′″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., arylsubstituted with 1-3 halogens, substituted or unsubstituted alkyl,alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″, R″″ and R′″″groups when more than one of these groups is present. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR′″″—C(NR′R″R′″)═NR″″,—NR″″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR″SO₂R′, —CN,—NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in anumber ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, R″″ and R′″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,R″″ and R″ groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅or C₆ alkyl.

“Ring” as used herein, means a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. A ringincludes fused ring moieties. The number of atoms in a ring is typicallydefined by the number of members in the ring. For example, a “5- to7-membered ring” means there are 5 or 6 or 7 atoms in the encirclingarrangement. Unless otherwise specified, the ring optionally includes aheteroatom. Thus, the term “5- to 7-membered ring” includes, for examplephenyl, pyridinyl and piperidinyl. The term “5- to 7-memberedheterocycloalkyl ring”, on the other hand, would include pyridinyl andpiperidinyl, but not phenyl. The term “ring” further includes a ringsystem comprising more than one “ring”, wherein each “ring” isindependently defined as above.

As used herein, the term “heteroatom” includes atoms other than carbon(C) and hydrogen (H). Examples include oxygen (O), nitrogen (N) sulfur(S), silicon (Si), germanium (Ge), aluminum (Al).

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include triflate, chloro, bromoand iodo groups; sulfonic ester groups, such as mesylate, tosylate,brosylate, nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl and substituted or unsubstitutedheterocycloalkyl groups.

By “effective” amount of a drug, formulation, or permeant is meant asufficient amount of an active agent to provide the desired local orsystemic effect. A “pharmaceutically effective,” or “therapeuticallyeffective” amount refers to the amount of drug needed to effect thedesired therapeutic result.

The term “pharmaceutically acceptable salt” is meant to include a saltof a compound of the invention which is prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino (suchas choline or diethylamine or amino acids such as d-arginine,1-arginine, d-lysine, 1-lysine), or magnesium salt, or a similar salt.When compounds of the invention contain relatively basicfunctionalities, acid addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, for example, Bergeet al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompounds in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the invention provides compounds which are ina prodrug form. Prodrugs of the compounds described herein readilyundergo chemical changes under physiological conditions to provide thecompounds of the invention. Additionally, prodrugs can be converted tothe compounds of the invention by chemical or biochemical methods in anex vivo environment.

Certain compounds of the invention can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the invention. Certain compounds of the invention may exist inmultiple crystalline or amorphous forms.

Certain compounds of the invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the invention. The graphic representations of racemic,ambiscalemic and scalemic or enantiomerically pure compounds used hereinare taken from Maehr, J. Chem. Ed. 1985, 62: 114-120.

Solid and broken wedges are used to denote the absolute configuration ofa stereocenter unless otherwise noted. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are included.

Compounds of the invention can exist in particular geometric orstereoisomeric forms. The invention contemplates all such compounds,including cis- and trans-isomers, (−)- and (+)-enantiomers, (R)- and(S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, such as enantiomericallyor diastereomerically enriched mixtures, as falling within the scope ofthe invention. Additional asymmetric carbon atoms can be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

Optically active (R)- and (S)-isomers and d and l isomers can beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If, for instance, a particular enantiomer of acompound of the invention is desired, it can be prepared by asymmetricsynthesis, or by derivatization with a chiral auxiliary, where theresulting diastereomeric mixture is separated and the auxiliary groupcleaved to provide the pure desired enantiomers. Alternatively, wherethe molecule contains a basic functional group, such as an amino group,or an acidic functional group, such as a carboxyl group, diastereomericsalts can be formed with an appropriate optically active acid or base,followed by resolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means known in the art, andsubsequent recovery of the pure enantiomers. In addition, separation ofenantiomers and diastereomers is frequently accomplished usingchromatography employing chiral, stationary phases, optionally incombination with chemical derivatization (e.g., formation of carbamatesfrom amines).

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). The compounds may also be labeled with stableisotopes such as deuterium. All isotopic variations of the compounds ofthe invention, whether radioactive or not, are intended to beencompassed within the scope of the invention.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable vehicle” refers to any formulation or carrier medium thatprovides the appropriate delivery of an effective amount of an activeagent as defined herein, does not interfere with the effectiveness ofthe biological activity of the active agent, and that is sufficientlynon-toxic to the animal. Representative carriers include water, oils,both vegetable and mineral, cream bases, lotion bases, ointment basesand the like. These bases include suspending agents, thickeners,penetration enhancers, and the like. Their formulation is well known tothose in the pharmaceutical arts. Additional information concerningcarriers can be found in Remington: The Science and Practice ofPharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005) which isincorporated herein by reference.

The term “pharmaceutically acceptable additive” refers to preservatives,antioxidants, fragrances, emulsifiers, dyes and excipients known or usedin the field of drug formulation and that do not unduly interfere withthe effectiveness of the biological activity of the active agent, andthat is sufficiently non-toxic to the animal. Additives for topicalformulations are well-known in the art, and may be added to the topicalcomposition, as long as they are pharmaceutically acceptable and notdeleterious to the epithelial cells or their function. Further, theyshould not cause deterioration in the stability of the composition. Forexample, inert fillers, anti-irritants, tackifiers, excipients,fragrances, opacifiers, antioxidants, gelling agents, stabilizers,surfactant, emollients, coloring agents, preservatives, bufferingagents, other permeation enhancers, and other conventional components oftopical or transdermal delivery formulations as are known in the art.

The terms “enhancement,” “penetration enhancement” or “permeationenhancement” relate to an increase in the permeability of the skin,nail, hair, claw or hoof to a drug, so as to increase the rate at whichthe drug permeates through the skin, nail, hair, claw or hoof. Theenhanced permeation effected through the use of such enhancers can beobserved, for example, by measuring the rate of diffusion of the drugthrough animal skin, nail, hair, claw or hoof using a diffusion cellapparatus. A diffusion cell is described by Merritt et al. DiffusionApparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp.161-162. The term “permeation enhancer” or “penetration enhancer”intends an agent or a mixture of agents, which, alone or in combination,act to increase the permeability of the skin, nail, hair or hoof to adrug.

The term “excipients” is conventionally known to mean carriers, diluentsand/or vehicles used in formulating drug compositions effective for thedesired use.

The terms “effective amount” or a “therapeutically effective amount” ofa drug or pharmacologically active agent refers to a nontoxic butsufficient amount of the drug or agent to provide the desired effect. Inthe oral dosage forms of the present disclosure, an “effective amount”of one active of the combination is the amount of that active that iseffective to provide the desired effect when used in combination withthe other active of the combination. The amount that is “effective” willvary from subject to subject, depending on the age and general conditionof the individual, the particular active agent or agents, and theappropriate “effective” amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation.

The phrases “active ingredient”, “therapeutic agent”, “active”, or“active agent” mean a chemical entity which can be effective in treatinga targeted disorder, disease or condition.

The phrase “pharmaceutically acceptable” means moieties or compoundsthat are, within the scope of medical judgment, suitable for use inhumans without causing undesirable biological effects such as unduetoxicity, irritation, allergic response, and the like, for example.

The phrase “unit”, as used herein, refers to the number of discreteobjects to be administered which comprise the dosage form. In someembodiments, the dosage form includes a compound of the invention in onecapsule. This is a single unit. In some embodiments, the dosage formincludes a compound of the invention as part of a therapeuticallyeffective dosage of a cream or ointment. This is also a single unit. Insome embodiments, the dosage form includes a compound of the inventionand another active ingredient contained within one capsule, or as partof a therapeutically effective dosage of a cream or ointment. This is asingle unit, whether or not the interior of the capsule includesmultiple discrete granules of the active ingredient. In someembodiments, the dosage form includes a compound of the invention in onecapsule, and the active ingredient in a second capsule. This is a twounit dosage form, such as two capsules or tablets, and so such units arecontained in a single package. Thus the term ‘unit’ refers to the objectwhich is administered to the animal, not to the interior components ofthe object.

“Biological medium,” as used herein refers to both in vitro and in vivobiological milieus. Exemplary in vitro “biological media” include, butare not limited to, cell culture, tissue culture, homogenates, plasmaand blood. In vivo applications are generally performed in mammals,preferably humans.

“Salt counterion”, as used herein, refers to positively charged ionsthat associate with a compound of the invention. Examples of saltcounterions include H⁺, H₃O⁺, ammonium, potassium, calcium, magnesium,organic amino (such as choline or diethylamine or amino acids such asd-arginine, l-arginine, d-lysine, l-lysine), and sodium.

II. Introduction

The invention provides tetrahydroisoquinolines, as well aspharmaceutical formulations containing such compounds or combinations ofthese compounds with at least one additional therapeutically effectiveagent, can be used for, among other things, treating viral infections.

III. The Compounds III. a)

In one aspect, the invention provides a compound of the invention. In anexemplary embodiment, the invention is a compound described herein. Inan exemplary embodiment, the invention is a compound according to aformula described herein.

In an exemplary embodiment, the invention provides a compound of theformula which is:

in which

-   -   R¹ is H or unsubstituted alkoxy or phenyl substituted alkoxy,    -   R² is H or CF₃ or unsubstituted alkoxy or phenyl substituted        alkoxy,    -   R³ is H or —C(O)OR⁴ or —C(O)R⁴ or —C(O)NR⁴R⁵, wherein        -   R⁴ and R⁵ are independently selected from unsubstituted            alkyl, unsubstituted phenyl, or unsubstituted pyridinyl;    -   A is substituted or unsubstituted phenyl or substituted or        unsubstituted pyrazole or substituted or unsubstituted pyridinyl        or substituted or unsubstituted thienyl or substituted or        unsubstituted pyrimidinyl or substituted or unsubstituted        pyrrole or substituted or unsubstituted thiazolyl        Also provided are hydrates, salts and solvates of these        compounds.

In an exemplary embodiment, A, R² and R³ are as described herein, and R¹is —CH₃. In an exemplary embodiment, A, R² and R³ are as describedherein, and R¹ is

In an exemplary embodiment, A, R² and R³ are as described herein, and R¹is H.

In an exemplary embodiment, A, R¹ and R³ are as described herein, and R²is —CH₃. In an exemplary embodiment, A, R¹ and R³ are as describedherein, and R² is

In an exemplary embodiment, A, R¹ and R³ are as described herein, and R²is H.

In an exemplary embodiment, A, R¹ and R² are as described herein, and R³is H. In an exemplary embodiment, A, R¹ and R² are as described herein,and R³ is —C(O)OCH₃. In an exemplary embodiment, A, R¹ and R² are asdescribed herein, and R³ is —C(O)OC(CH₃)₃. In an exemplary embodiment,A, R¹ and R² are as described herein, and R³ is

In an exemplary embodiment, A, R¹ and R² are as described herein, and R³is

In an exemplary embodiment, A, R¹ and R² are as described herein, and R³is

In an exemplary embodiment, A, R¹ and R² are as described herein, and R³is

In an exemplary embodiment, A, R¹ and R² are as described herein, and R³is

In an exemplary embodiment, A, R¹ and R² are as described herein, and R³is

In an exemplary embodiment, A, R¹ and R² are as described herein, and R³is

In an exemplary embodiment, A, R¹ and R² are as described herein, and R³is

In an exemplary embodiment, A, R¹ and R² are as described herein, and R³is

In an exemplary embodiment, A, R¹ and R² are as described herein, and R³is —C(O)NH₂. In an exemplary embodiment, A, R¹ and R² are as describedherein, and R³ is—C(O)NHC(CH₃)₃. In an exemplary embodiment, A, R¹ and R² are asdescribed herein, and R³ is —(CH₂)_(n)CH₃, wherein n is an integerselected from 0 or 1 or 2 or 3 or 4 or 5. In an exemplary embodiment, A,R¹ and R² are as described herein, and R³ is —(CH₂)_(n)CH₃, wherein n isan integer selected from 6 or 7 or 8 or 9 or 10. In an exemplaryembodiment, A, R¹ and R² are as described herein, and R³ is—(CH₂)_(n)CH₃, wherein n is an integer selected from 2 or 3 or 4. In anexemplary embodiment, A, R¹ and R² are as described herein, and R³ is—(CH₂)₃CH₃. In an exemplary embodiment, A, R¹ and R² are as describedherein, and R³ is —CH₃.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein each R¹⁰, R¹¹ and R¹² is independently selected from H orhalogen or unsubstituted alkyl or halogen-substituted alkyl orunsubstituted alkoxy or phenyl-substituted alkoxy. In an exemplaryembodiment, R¹¹ and R¹² are as described herein, and R¹⁰ is —CH₃. In anexemplary embodiment, R¹¹ and R¹² are as described herein, and R¹⁰ is—CH₂CH₃. In an exemplary embodiment, R¹¹ and R¹² are as describedherein, and R¹⁰ is tert-butyl. In an exemplary embodiment, and R¹² areas described herein, and R¹⁰ is —CF₃. In an exemplary embodiment, R¹¹and R¹² are as described herein, and R¹⁰ is —OBn. In an exemplaryembodiment, and R¹² are as described herein, and R¹⁰ is halogen. In anexemplary embodiment, R¹¹ and R¹² are as described herein, and R¹⁰ isCl. In an exemplary embodiment, R¹¹ and R¹² are as described herein, andR¹⁰ is H. In an exemplary embodiment, R¹⁰ and R¹² are as describedherein, and R¹¹ is —OCH₃. In an exemplary embodiment, R¹⁰ and R¹² are asdescribed herein, and R¹¹ is —OBn. In an exemplary embodiment, R¹⁰ andR¹² are as described herein, and R¹¹ is H. In an exemplary embodiment,R¹⁰ and R¹¹ are as described herein, and R¹² is —OCH₃. In an exemplaryembodiment, R¹⁰ and R¹¹ are as described herein, and R¹² is —OBn. In anexemplary embodiment, R¹⁰ and R¹¹ are as described herein, and R¹² ishalogen. In an exemplary embodiment, R¹⁰ and R¹¹ are as describedherein, and R¹² is H. In an exemplary embodiment, R¹⁰ is unsubstitutedC₁-C₆ alkoxy, R¹¹ is H, and R¹² is unsubstituted C₁-C₆ alkoxy. In anexemplary embodiment, R¹⁰ is methoxy, R¹¹ is H, and R¹² is unsubstitutedC₁-C₆ alkoxy. In an exemplary embodiment, R¹⁰ is unsubstituted C₁-C₆alkoxy, R¹¹ is H, and R¹² is methoxy. In an exemplary embodiment, R¹⁰ ismethoxy, R¹¹ is H, and R¹² is methoxy. In an exemplary embodiment, R¹⁰is H, R¹¹ is unsubstituted C₁-C₆ alkoxy, and R¹² is unsubstituted C₁-C₆alkoxy. In an exemplary embodiment, R¹⁰ is H, R¹¹ is methoxy, and R¹² isunsubstituted C₁-C₆ alkoxy. In an exemplary embodiment, R¹⁰ is H, R¹¹ isunsubstituted C₁-C₆ alkoxy, and R¹² is methoxy. In an exemplaryembodiment, R¹⁰ is H, R¹¹ is methoxy, and R¹² is methoxy. In anexemplary embodiment, R¹⁰ is H, R¹¹ is unsubstituted C₄-C₆ alkoxy, andR¹² is unsubstituted C₁-C₆ alkoxy. In an exemplary embodiment, R¹⁰ is H,R¹¹ is methoxy, and R¹² is unsubstituted C₄-C₆ alkoxy. In an exemplaryembodiment, R¹⁰ is H, R¹¹ is butoxy, and R¹² is methoxy. In an exemplaryembodiment, R¹⁰ is H, R¹¹ is butoxy, and R¹² is methoxy. In an exemplaryembodiment, R¹⁰ is H, R¹¹ is halogen, and R¹² is unsubstituted C₁-C₆alkoxy. In an exemplary embodiment, R¹⁰ is H, R¹¹ is unsubstituted C₁-C₆alkoxy, and R¹² is halogen. In an exemplary embodiment, R¹⁰ is H, R¹¹ ismethoxy, and R¹² is halogen. In an exemplary embodiment, R¹⁰ is H, R¹¹is halogen, and R¹² is methoxy. In an exemplary embodiment, R¹⁰ is H,R¹¹ is F, and R¹² is unsubstituted C₁-C₆ alkoxy. In an exemplaryembodiment, R¹⁰ is H, R¹¹ is unsubstituted C₁-C₆ alkoxy, and R¹² is F.In an exemplary embodiment, R¹⁰ is unsubstituted C₁-C₆ alkyl, R¹¹ isunsubstituted C₁-C₆ alkoxy, and R¹² is unsubstituted C₁-C₆ alkoxy. In anexemplary embodiment, R¹⁰ is unsubstituted C₁-C₃ alkyl, R¹¹ isunsubstituted C₁-C₃ alkoxy, and R¹² is unsubstituted C₁-C₃ alkoxy. In anexemplary embodiment, R¹⁰ is methyl, R¹¹ is unsubstituted C₁-C₆ alkoxy,and R¹² is unsubstituted C₁-C₆ alkoxy. In an exemplary embodiment, R¹⁰is unsubstituted C₁-C₆ alkyl, R¹¹ is unsubstituted C₃-C₆ alkoxy, and R¹²is unsubstituted C₁-C₃ alkoxy.In an exemplary embodiment, R¹⁰ is unsubstituted C₁-C₆ alkyl, R¹¹ isbutoxy, and R¹² is unsubstituted C₁-C₃ alkoxy. In an exemplaryembodiment, R¹⁰ is unsubstituted C₁-C₆ alkyl, R¹¹ is unsubstituted C₁-C₆alkoxy, and R¹² is methoxy. In an exemplary embodiment, R¹⁰ is methyl,is unsubstituted C₁-C₆ alkoxy, and R¹² is methoxy. In an exemplaryembodiment, R¹⁰ is methyl, R¹¹ is butoxy, and R¹² is methoxy. In an H,exemplary embodiment, R¹⁰ is H R¹¹ is unsubstituted C₁-C₆ alkoxy, andR¹² is unsubstituted C₁-C₆ alkoxy. In an exemplary embodiment, R¹⁰ is H,R¹¹ is unsubstituted C₁-C₃ alkoxy, and R¹² is unsubstituted C₁-C₃alkoxy. In an exemplary embodiment, R¹⁰ is H, R¹¹ is unsubstituted C₁-C₃alkoxy, and R¹² is methoxy. In an exemplary embodiment, R¹⁰ is H, R¹¹ ismethoxy, and R¹² is unsubstituted C₁-C₃ alkoxy. In an exemplaryembodiment, R¹⁰ is H R¹¹ is methoxy, and R¹² is methoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is NR²⁰R²¹, wherein R²⁰ and R²¹ are each independentlyselected from H or unsubstituted alkyl, and wherein R¹¹ and R¹² are eachindependently selected from H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy. In an exemplary embodiment, R¹⁰ is N(CH₃)₂, wherein R²⁰ and R²¹are each independently selected from H or unsubstituted alkyl, andwherein R¹¹ and R¹² are each independently selected from H or halogen orunsubstituted alkyl or halogen-substituted alkyl or unsubstituted alkoxyor phenyl-substituted alkoxy. In an exemplary embodiment, R¹⁰ is NH₂,wherein R²⁰ and R²¹ are each independently selected from H orunsubstituted alkyl, and wherein R¹¹ and R¹² are each independentlyselected from H or halogen or unsubstituted alkyl or halogen-substitutedalkyl or unsubstituted alkoxy or phenyl-substituted alkoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein each R¹¹, R¹², and R¹³ is independently selected from H orhalogen or unsubstituted alkyl or halogen-substituted alkyl orunsubstituted alkoxy or phenyl-substituted alkoxy, wherein at least oneof said R¹¹ or R¹² or R¹³ is unsubstituted alkoxy. In an exemplaryembodiment, R¹¹ and R¹² are as described herein, and R¹³ is —CH₃. In anexemplary embodiment, R¹¹ and R¹² are as described herein, and R¹³ is—CH₂CH₃. In an exemplary embodiment, R¹¹ and R¹² are as describedherein, and R¹³ is —OCH₃. In an exemplary embodiment, R¹¹ and R¹² are asdescribed herein, and R¹³ is —OCH₂CH₃. In an exemplary embodiment, R¹¹is unsubstituted C₁-C₆ alkoxy, R¹² is unsubstituted C₁-C₆ alkoxy, andR¹³ is unsubstituted C₁-C₆ alkoxy. In an exemplary embodiment, R¹¹ ismethoxy, R¹² is unsubstituted C₁-C₆ alkoxy, and R¹³ is unsubstitutedC₁-C₆ alkoxy. In an exemplary embodiment, R¹¹ is unsubstituted C₁-C₃alkoxy, R¹² is methoxy, and R¹³ is unsubstituted C₁-C₃ alkoxy. In anexemplary embodiment, R¹¹ is unsubstituted C₁-C₃ alkoxy, R¹² isunsubstituted C₁-C₃ alkoxy, and R¹³ is unsubstituted C₁-C₃ alkoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹² is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

wherein R¹² is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

wherein R¹² is C₁-C₆ alkoxy. In an exemplary embodiment, R¹, R² and R³are as described herein, and A is

wherein R¹² is C₁-C₆ alkoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹² is unsubstituted C₁-C₆ alkoxy. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is

wherein R¹² is unsubstituted C₁-C₃ alkoxy. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is

wherein R¹² is methoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy, R¹¹ is unsubstituted C₁-C₆ alkoxy and R¹² is H or halogen orunsubstituted alkyl or halogen-substituted alkyl or unsubstituted alkoxyor phenyl-substituted alkoxy. In an exemplary embodiment, R¹⁰ is H orhalogen or unsubstituted alkyl or halogen-substituted alkyl orunsubstituted alkoxy or phenyl-substituted alkoxy, R¹¹ is unsubstitutedethoxy or propoxy or isopropoxy or butoxy or isobutoxy or t-butoxy andR¹² is H or halogen or unsubstituted alkyl or halogen-substituted alkylor unsubstituted alkoxy or phenyl-substituted alkoxy. In an exemplaryembodiment, R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy, is unsubstituted methoxy and R¹² is H or halogen orunsubstituted alkyl or halogen-substituted alkyl or unsubstituted alkoxyor phenyl-substituted alkoxy. In an exemplary embodiment, R¹⁰ is C₁-C₆unsubstituted alkoxy, R¹¹ is C₁-C₆ unsubstituted alkoxy and R¹² is C₁-C₆unsubstituted alkoxy. In an exemplary embodiment, R¹⁰ is C₁-C₃unsubstituted alkoxy, R¹¹ is C₁-C₃ unsubstituted alkoxy and R¹² is C₁-C₃unsubstituted alkoxy. In an exemplary embodiment, R¹⁰ is H or halogen orunsubstituted alkyl or halogen-substituted alkyl or unsubstituted alkoxyor phenyl-substituted alkoxy, R¹¹ is methoxy and R¹² is methoxy. In anexemplary embodiment, R¹⁰ is C₁-C₆ unsubstituted alkoxy, is methoxy andR¹² is methoxy. In an exemplary embodiment, R¹⁰ is C₁-C₃ unsubstitutedalkoxy, R¹¹ is methoxy and R¹² is methoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy, R¹² is unsubstituted C₁-C₆ alkoxy and R¹¹ is H or halogen orunsubstituted alkyl or halogen-substituted alkyl or unsubstituted alkoxyor phenyl-substituted alkoxy. In an exemplary embodiment, R¹⁰ is H orhalogen or unsubstituted alkyl or halogen-substituted alkyl orunsubstituted alkoxy or phenyl-substituted alkoxy, R¹² is unsubstitutedethoxy or propoxy or isopropoxy or butoxy or isobutoxy or t-butoxy andR¹¹ is H or halogen or unsubstituted alkyl or halogen-substituted alkylor unsubstituted alkoxy or phenyl-substituted alkoxy. In an exemplaryembodiment, R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy, R¹² is unsubstituted methoxy and R¹¹ is H or halogen orunsubstituted alkyl or halogen-substituted alkyl or unsubstituted alkoxyor phenyl-substituted alkoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

wherein R¹⁰ is unsubstituted C₁-C₆ alkyl or unsubstituted C₁-C₆ alkoxy.In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is unsubstituted C₁-C₃ alkyl or unsubstituted C₁-C₃ alkoxy.In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is methyl or methoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

wherein R¹⁰ is halogen or unsubstituted alkyl or halogen-substitutedalkyl or unsubstituted alkoxy or phenyl-substituted alkoxy. In anexemplary embodiment, R′, R² and R³ are as described herein, and A is

wherein R¹⁰ is C₁-C₃ unsubstituted alkyl.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

wherein R¹⁰ is unsubstituted C₁-C₆ alkyl or unsubstituted C₁-C₆ alkoxy.In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is unsubstituted C₁-C₃ alkyl. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is

wherein R¹⁰ is methyl or methoxy.In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is unsubstituted C₁-C₃ alkoxy.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is H or halogen or unsubstituted alkyl orhalogen-substituted alkyl or unsubstituted alkoxy or phenyl-substitutedalkoxy. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

wherein R¹⁰ is halogen or unsubstituted alkyl or halogen-substitutedalkyl or unsubstituted alkoxy or phenyl-substituted alkoxy. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹⁰ is C₁-C₃ unsubstituted alkyl. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is

wherein R¹⁰ is unsubstituted C₁-C₆ alkyl or unsubstituted C₁-C₆ alkoxy.In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹⁰ is unsubstituted C₁-C₃ alkyl. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is

wherein R¹⁰ is methyl or methoxy. In an exemplary embodiment, R¹, R² andR³ are as described herein, and A is

wherein R¹⁰ is unsubstituted C₁-C₃ alkoxy. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹² is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. In an exemplary embodiment, R¹, R² and R³ areas described herein, and A is

wherein R¹² is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. In an exemplary embodiment, R¹, R² and R³ areas described herein, and A is

wherein R¹² is a substituted or unsubstituted nitrogen-containing 4-8membered ring. In an exemplary embodiment, R¹, R² and R³ are asdescribed herein, and A is

wherein R¹² is a substituted or unsubstituted nitrogen-containing 5-6membered ring. In an exemplary embodiment, R¹, R² and R³ are asdescribed herein, and A is

wherein R¹² is substituted or unsubstituted pyridinyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is substituted or unsubstituted pyridin-4-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is substituted or unsubstituted pyridin-3-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is substituted or unsubstituted pyridin-2-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is unsubstituted pyridinyl.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹² is substituted or unsubstituted pyrimidinyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is substituted or unsubstituted pyrimidin-5-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is substituted or unsubstituted pyrimidin-2-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is substituted or unsubstituted pyrimidin-4-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is unsubstituted pyrimidin-5-yl. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is

wherein R¹² is unsubstituted pyrimidin-2-yl. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is

wherein R¹² is unsubstituted pyrimidin-4-yl.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹² is substituted or unsubstituted imidazolyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is substituted or unsubstituted imidazol-1-yl.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹² is substituted or unsubstituted indolyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is indolyl substituted with —C(O)OR²², wherein R²² is C₁-C₆alkyl. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

wherein R¹² is indolyl substituted with —C(O)OR²², wherein R²² ist-butyl. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

wherein R¹² is indolyl substituted with C₁-C₆ alkyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is indolyl substituted with methyl.In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹² is substituted or unsubstituted indol-3-yl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is indol-3-yl substituted with C₁-C₆ alkyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is indol-3-yl substituted with methyl.In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹² is indol-3-yl substituted with —C(O)OR²², wherein R²² isC₁-C₆ alkyl. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

wherein R¹² is indol-3-yl substituted with —C(O)OR²², wherein R²² ist-butyl.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹² is substituted or unsubstituted pyrrolopyridinyl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is pyrrolopyridinyl substituted with C₁-C₆ alkyl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is pyrrolopyridinyl substituted methyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is pyrrolopyridinyl substituted with —C(O)OR²², wherein R²²is C₁-C₆ alkyl. In an exemplary embodiment, R¹, R² and R³ are asdescribed herein, and A is

wherein R¹² is pyrrolopyridinyl substituted with —C(O)OR²², wherein R²²is t-butyl. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

wherein R¹² is substituted or unsubstituted pyrrolopyridin-3-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is pyrrolopyridin-3-yl substituted with C₁-C₆ alkyl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is pyrrolopyridin-3-yl substituted with methyl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is pyrrolopyridin-3-yl substituted with —C(O)OR²², whereinR²² is C₁-C₆ alkyl. In an exemplary embodiment, R¹, R² and R³ are asdescribed herein, and A is

wherein R¹² is pyrrolopyridin-3-yl substituted with —C(O)OR²², whereinR²² is t-butyl.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹² is substituted or unsubstituted triazolyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹² is triazol-1-yl.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

wherein R¹¹ is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. In an exemplary embodiment, R¹, R² and R³ areas described herein, and A is

wherein R¹¹ is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. In an exemplary embodiment, R¹, R² and R³ areas described herein, and A is

wherein R¹¹ is a substituted or unsubstituted nitrogen-containing 4-8membered ring. In an exemplary embodiment, R¹, R² and R³ are asdescribed herein, and A is

wherein R¹¹ is a substituted or unsubstituted nitrogen-containing 5-6membered ring. In an exemplary embodiment, R¹, R² and R³ are asdescribed herein, and A is

wherein is substituted or unsubstituted pyridinyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹¹ is substituted or unsubstituted pyridin-4-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹¹ is substituted or unsubstituted pyridin-3-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹¹ is substituted or unsubstituted pyridin-2-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

wherein R¹¹ is unsubstituted pyridinyl.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais unsubstituted pyrazolyl. In an exemplary embodiment, R¹, R² and R³are as described herein, and A is substituted pyrazolyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is pyrazolylsubstituted with C₁-C₃ alkyl. In an exemplary embodiment, R¹, R² and R³are as described herein, and A is pyrazolyl substituted with methyl. Inan exemplary embodiment, R¹, R² and R³ are as described herein, and A is

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais unsubstituted pyridinyl. In an exemplary embodiment, R¹, R² and R³are as described herein, and A is unsubstituted pyridin-3-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A isunsubstituted pyridin-4-yl. In an exemplary embodiment, R¹, R² and R³are as described herein, and A is substituted pyridinyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is substitutedpyridin-4-yl. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is substituted pyridin-3-yl. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is pyridinyl substitutedwith C₁-C₃ alkyloxy. In an exemplary embodiment, R¹, R² and R³ are asdescribed herein, and A is pyridinyl substituted with two C₁-C₃alkyloxy. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is pyridinyl substituted with methoxy. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is pyridin-3-ylsubstituted with methoxy. In an exemplary embodiment, R¹, R² and R³ areas described herein, and A is pyridin-4-yl substituted with methoxy. Inan exemplary embodiment, R¹, R² and R³ are as described herein, and A ispyridin-3-yl substituted with two methoxy. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is pyridin-4-yl substitutedwith two methoxy. In an exemplary embodiment, R¹, R² and R³ are asdescribed herein, and A is

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais pyridinyl substituted with NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are eachindependently selected from H or unsubstituted C₁-C₃ alkyl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A ispyridinyl substituted with two NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are eachindependently selected from H or unsubstituted C₁-C₃ alkyl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A ispyridinyl substituted with N(CH₃)₂. In an exemplary embodiment, R¹, R²and R³ are as described herein, and A is pyridinyl substituted with NH₂.In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais pyridin-3-yl substituted with N(CH₃)₂. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is pyridin-4-yl substitutedwith N(CH₃)₂. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is pyridin-3-yl substituted with NH₂. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is pyridin-4-ylsubstituted with NH₂. In an exemplary embodiment, R¹, R² and R³ are asdescribed herein, and A is

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais unsubstituted pyrimidinyl. In an exemplary embodiment, R¹, R² and R³are as described herein, and A is unsubstituted pyrimidin-5-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A isunsubstituted pyrimidin-4-yl. In an exemplary embodiment, R¹, R² and R³are as described herein, and A is substituted pyrimidinyl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A issubstituted pyrimidin-5-yl. In an exemplary embodiment, R¹, R² and R³are as described herein, and A is substituted pyrimidin-4-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A ispyrimidinyl substituted with C₁-C₃ alkyloxy. In an exemplary embodiment,R¹, R² and R³ are as described herein, and A is pyrimidinyl substitutedwith two C₁-C₃ alkyloxy. In an exemplary embodiment, R¹, R² and R³ areas described herein, and A is pyrimidinyl substituted with methoxy. Inan exemplary embodiment, R¹, R² and R³ are as described herein, and A ispyrimidin-5-yl substituted with methoxy. In an exemplary embodiment, R¹,R² and R³ are as described herein, and A is pyrimidin-4-yl substitutedwith methoxy. In an exemplary embodiment, R¹, R² and R³ are as describedherein, and A is

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais pyrimidinyl substituted with substituted phenyl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is pyrimidinylsubstituted with unsubstituted phenyl. In an exemplary embodiment, R¹,R² and R³ are as described herein, and A is pyrimidinyl substituted withunsubstituted phenyl substituted with C₁-C₃ alkyloxy. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A is pyrimidinylsubstituted with unsubstituted phenyl substituted with methoxy. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A is

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais unsubstituted thienyl. In an exemplary embodiment, R¹, R² and R³ areas described herein, and A is unsubstituted thien-2-yl. In an exemplaryembodiment, R¹, R² and R³ are as described herein, and A isunsubstituted thien-3-yl. In an exemplary embodiment, R¹, R² and R³ areas described herein, and A is thienyl substituted with C₁-C₃ alkyl. Inan exemplary embodiment, R¹, R² and R³ are as described herein, and A isthien-2-yl substituted with C₁-C₃ alkyl. In an exemplary embodiment, R¹,R² and R³ are as described herein, and A is thien-3-yl substituted withC₁-C₃ alkyl.

In an exemplary embodiment, R¹, R² and R³ are as described herein, and Ais unsubstituted thiazolyl. In an exemplary embodiment, R¹, R² and R³are as described herein, and A is unsubstituted thiazol-4-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A isunsubstituted thiazol-5-yl. In an exemplary embodiment, R¹, R² and R³are as described herein, and A is unsubstituted thiazol-2-yl. In anexemplary embodiment, R¹, R² and R³ are as described herein, and A isthiazolyl substituted with C₁-C₃ alkyl. In an exemplary embodiment, R¹,R² and R³ are as described herein, and A is thiazol-4-yl substitutedwith C₁-C₃ alkyl. In an exemplary embodiment, R¹, R² and R³ are asdescribed herein, and A is thiazol-5-yl substituted with C₁-C₃ alkyl. Inan exemplary embodiment, R¹, R² and R³ are as described herein, and A isthiazol-2-yl substituted with C₁-C₃ alkyl.

In an exemplary embodiment, the compound has the formula which is:

wherein R², R³ and A are as described herein, or a hydrate, solvate, orsalt thereof.

In an exemplary embodiment, the compound has the formula which is:

wherein R¹, R³ and A are as described herein, or a hydrate, solvate, orsalt thereof.

In an exemplary embodiment, the compound has the formula which is:

wherein R¹, R² and A are as described herein, or a hydrate, solvate, orsalt thereof.

In an exemplary embodiment, the compound has the formula which is:

wherein R¹, R², R³, R¹⁰, R¹¹ and R¹² are as described herein, or ahydrate, solvate, or salt thereof.

In an exemplary embodiment, the compound has the formula which is:

wherein R³ and A are as described herein, or a hydrate, solvate, or saltthereof.

In an exemplary embodiment the compound has the formula which is:

wherein R² and A are as described herein, or a hydrate, solvate, or saltthereof.

In an exemplary embodiment, the compound has the formula which is:

wherein R¹ and A are as described herein, or a hydrate, solvate, or saltthereof.

In an exemplary embodiment, the compound has the formula which is:

wherein A is as described herein, or a hydrate, solvate, or saltthereof.

In an exemplary embodiment, the compound has the formula which is:

or a hydrate, solvate, or salt thereof.

In an exemplary embodiment, the compound has the formula which is:

or a hydrate, solvate, or salt thereof.

In an exemplary embodiment, the compound has the formula which is:

or a hydrate, solvate, or salt thereof.

In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof, or a combination thereof.In an exemplary embodiment, the invention provides a compound describedin a Figure provided herein, or a salt, hydrate or solvate thereof, or acombination thereof. In an exemplary embodiment, the invention providesa compound described herein, or a salt, hydrate or solvate thereof. Inan exemplary embodiment, the invention provides a compound describedherein, or a salt thereof. In an exemplary embodiment, the salt is apharmaceutically acceptable salt. In an exemplary embodiment, theinvention provides a compound described herein, or a hydrate thereof. Inan exemplary embodiment, the invention provides a compound describedherein, or a solvate thereof. In an exemplary embodiment, the inventionprovides a compound described herein, or a prodrug thereof. In anexemplary embodiment, the invention provides a salt of a compounddescribed herein. In an exemplary embodiment, the invention provides apharmaceutically acceptable salt of a compound described herein. In anexemplary embodiment, the invention provides a hydrate of a compounddescribed herein. In an exemplary embodiment, the invention provides asolvate of a compound described herein. In an exemplary embodiment, theinvention provides a prodrug of a compound described herein.

In an exemplary embodiment, alkyl is linear alkyl. In another exemplaryembodiment, alkyl is branched alkyl.

In an exemplary embodiment, heteroalkyl is linear heteroalkyl. Inanother exemplary embodiment, heteroalkyl is branched heteroalkyl.

III.b) Preparation of Compounds

Compounds of use in the invention can be prepared using commerciallyavailable starting materials, known intermediates, or by using thesynthetic methods described herein, or published in references describedand incorporated by reference herein.

A General Procedure to Make Compounds of the Invention General Procedurefor the Synthesis of Substituted Phenethyl Amines^(a)

A solution of the Benzaldehyde 1 (0.1 mol), Nitromethane (50 ml, 0.93mmol) and Ammonium acetate (0.26 mol) in Acetic acid (200 ml) wasrefluxed for 1 h. Upon cooling the product crystallized out of solution.The crystals were filtered out and washed with a small amount of etherto give a bright yellow nitrostyrene.

To a stirred solution of Lithium aluminum hydride (0.21 mol) inTetrahydrofuran (270 ml) was added dropwise a solution of the abovenitrostyrene (0.11 mol) in Tetrahydrofuran (200 ml). Upon completion thereaction mixture was refluxed with stirring for 16 h, cooled to roomtemperature and the excess hydride decomposed by the addition of aq.sat. Na₂SO₄. The mixture was filtered and the filtrate rotary evaporatedto an amber-brown oil (the title compound) 2 which was used withoutfurther purification.

General Procedure for the Synthesis of Substituted Cinammic Acids^(b)

A mixture of the Benzaldehyde 3 (30 mmol), Malonic acid (60 mmol),Pyridine (20 mL) and Piperidine (5 mmol) was stirred at 80° C. for 1 hfollowed by refluxing at 110-115° C. for an additional 3 h. The cooledreaction mixture was poured into water (250 mL) and acidified with conc.HCl. The resulting precipitate was filtered off and washed several timeswith water. It was redissolved in 2M NaOH, diluted with water, acidifiedwith conc. HCl. The solid precipitate was filtered washed several timeswith water, dried under high vacuum over P₂O₅ to afford the titledcompound 4.

Alternate Synthesis of Cinnamic Acids

The ethyl-2-(diethoxyphosphino)acetate was dissolved in THF and cooledto 0° C. To this mixture was added 1 equivalent of NaH (60% in mineraloil) in portions. The mixture immediately evolved of H₂ gas. After theaddition was complete, the mixture was stirred at room temperature for 1hour. To this mixture at 0° C. was added one equivalent of thebenzaldehyde. The mixture was stirred at 0° C. for 1 hour, then allowedto warm up to room temperature overnight. The mixture was pored over icewater and extracted with EtOAc. The combined organic layers were driedover MgSO₄, filtered and evaporated to give a residue, which waspurified by flash chromatography. The correct product was confirmed byLC-MS.

The resulting cinnamoyl ester was dissolved in a 1/1 mixture of EtOH and1M KOH solution and heated at 75° C. overnight. When all of the startingmaterial was consumed, the reaction was allowed to cool to roomtemperature and the EtOH was removed by evaporation. The resultingresidue was acidified with 2N H₃PO₄ and the product was either filteredoff to dry under vacuum or extracted with EtOAc, followed by drying overMgSO₄, filtration and evaporation. The correct product was confirmed byLC-MS.

General Procedure for the Synthesis of Substituted Cinnamides^(c)

To a stirred mixture of the substituted Phenethylamine 2 (0.48 mmol),substituted Cinnamic acid 4 (0.72 mmol), DIEA [420 uL (2.4 mmol)] & 10ml of DMF was added HATU (1 mmol). The reaction was stirred at rt for 1h and then diluted with 20 ml of EtOAc and washed 2× with sat NaCl. TheEtOAc layer was dried (Na₂SO₄) and the solvent removed yielding thetitle compound 6.

General Procedure for the Cyclization and Reduction of the SubstitutedCinnamides: Synthesis of Substituted Tetrahydroisoquinolines^(d)

To the substituted Cinnamide 6 (0.563 mmol) in ACN (13 ml) was added,under reflux, POCl₃ (3.9 mmol). The reaction was stirred at reflux for30 min and then rotary evaporated to dryness. The residue was taken upinto 10 ml of chloroform and was then treated with 20 ml of 2N KOH and50 mL of Et₂O. This mixture was rapidly stirred for 30 min at roomtemperature and the upper organic layer removed, washed with water,dried (Na₂SO₄) and the solvent removed. The resulting dark oil(Substituted Dihydroisoquinoline) was then dissolved into 8 ml of dryEtOH and then treated with NaBH₄ (0.395 mmol). The mixture was stirredfor 1 h at room temperature and the resulting solid was carefullyfiltered off and dried. The solid was triturated with 50/50 ACN/water,filtered and vacuum dried yielding the title compound 7.

General Synthesis of Dihydroisoquinolines^(e)—

The phenethylamine 2 was combined with ethyl formate (20 mL) and heatedat reflux overnight. The reaction was checked by TLC and LC-MS for theconsumption of starting material. The reaction was allowed to cool toroom temperature and the organic solvents were evaporated to five aresidue, which solidified on standing at room temperature. The correctproduct 8 was confirmed by LC-MS and was used in the next step withoutpurification.

The formamide was cyclized to the dihydroisoquinoline 9 by either of twomethods:

-   -   a. The phenethylformamide was combined with polyphosphoric acid        (PPA) and heated at 160° C. for 12 hours. The mixture was        allowed to cool to room temperature and poured over ice. The        mixture was made basic with NaOH solution and extracted with        EtOAc. The combined organic layers were dried over MgSO₄,        filtered and evaporated to give a residue. The residue was        purified by flash chromatography. The correct product 9 was        confirmed by LC-MS.    -   b. To a solution of the phenethylformamide in CH₂Cl₂ cooled to        0° C. was added 1 equivalent of POCl₃ dropwise. After the        addition, the reaction was stirred from 2 hrs to 18 hrs. The        reaction mixture was evaporated to dryness and the pH was        adjusted to 10 with NH₄OH solution. The mixture was extracted        with EtOAc and the combined organic layers were dried over        MgSO₄, filtered and evaporated. The residue was either        recrystallized or purified by flash chromatography. The correct        product 9 was confirmed by LC-MS.

Alternate Synthesis of Dihydoisoquinolines^(f)

Acetic acid/trifluoroacetic acid (4/1) was added to a mixture of thephenylethylamine 2 and 2 equivalents of hexamethylenetetramine. Theresulting solution was heated at reflux for 8 hours. The reaction wasallowed to cool to room temperature and water was added to the solution,which was extracted with dichloromethane. The combined organic layerswere washed with saturated NaHCO₃, and brine before drying over MgSO₄.The organic layer was filtered and evaporated to dryness. The residuewas purified by flash chromatography to give the desired product. Thecorrect product 9 was confirmed by LC-MS.

Synthesis of Cinnamoyl Bromide^(g)

A catalytic amount of triethylamine (5 mol %) was added to a solution ofthe acrylic acid in CH₂Cl₂. The mixture was stirred for 5 minutes beforeNBS (120 mol %) was added in portions. Within 5 minutes of the firstaddition, CO₂ gas evolved. After all of the NBS was added, the mixturewas allowed to stir overnight at room temperature. The organic solventwas evaporated and the residue was purified by flash chromatography togive very good yields of the desired cinnamoyl bromide.

General Method for Synthesis of Styrl-TetrahydroisoquinolineDerivatives^(h)

The bromovinylbenzene was dissolved in Et₂O and cooled to −78° C. underargon. To this mixture was added 2.2 equivalents of t-BuLi dropwise. Theresulting solution was stirred for 1 hour at −78° C. To this mixture wasadded a solution of 1 equivalent of the dihydroisoquinoline in THF. Atthe end of the addition, the mixture was allowed to stir at −78° C. for1 to 2 hours. The mixture was quenched by the direct addition of asaturated solution of NH₄Cl. The mixture was extracted with EtOAc andthe combined organic layers were dried over MgSO₄, filtered andevaporated to dryness. The residue was purified by flash chromatography(and Prep HPLC). The correct product was confirmed by LC-MS and/or H¹NMR.

Typical Julia-Kocienski Reaction Conditions:

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and the aldehyde (0.84 mmol) in THF (10 mL) wascooled to −35° C. with stirring under argon. To this mixture was added asolution of lithium bis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M inTHF) and the reaction mixture was stirred for 1 hour at −35° C. Thereaction was allowed to warm up to room temperature and the organicsolvent was evaporated to give a residue. The residue was dissolved (orsuspended) in 4M HCl dioxane (5 mL) and stirred at room temperatureuntil the reaction was completed. The organic layer was evaporated toleave a residue, which was purified by flash or reverse phasepreparatory chromatography.

Synthesis of key intermediate tert-butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate^(i)

a. Ethyl6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate^(f)

tert-Butyl N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]carbamate (8.9 g,24.89 mmol) was dissolved in CH₂Cl₂ (250 mL) and cooled to 0° C. withstirring under argon. To this solution was added ethyl 2-oxoacetate(9.86 mL, 49.84 mmol, 50% in Toluene), followed by the dropwise additionof BF₃-Et₂O (7.7 mL, 62.21 mmol) over 30 minutes. The mixture wasstirred for 1 hour at 0° C., then allowed to warm to room temperatureovernight. The organic layer was evaporated to give a residue, which waspurified by flash chromatography. The correct product was confirmed byLC-MS; M+1=342.

b. O2-tert-Butyl O1-ethyl6-benzyloxy-7-methoxy-3,4-dihydro-1H-isoquinoline-1,2-dicarboxylate

Ethyl 6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate(9.0 g, 26.63 mmol) was dissolved in CH₂Cl₂ (200 mL), followed by Et₃N(4.0 mL, 28.8 mmol) and Boc₂O (6.3 g, 28.8 mmol). The mixture wasstirred overnight at room temperature. The mixture was washed with 1MH₃PO₄ and brine. The organic layer was dried over MgSO4, filtered andevaporated to give the crude product, which was used without furtherpurification. LC-MS; M+1=442.

c.6-Benzyloxy-2-tert-butoxycarbonyl-7-methoxy-3,4-dihydro-1H-isoquinoline-1-carboxylicacid

O2-tert-Butyl O1-ethyl6-benzyloxy-7-methoxy-3,4-dihydro-1H-isoquinoline-1,2-dicarboxylate(11.0 g, 24.9 mmol) was dissolved in THF (50 mL), EtOH (50 mL) and H₂O(50 mL). To this solution was added solid KOH (3.8 g, 67.8 mmol) and themixture was stirred at room temperature for 24 hours. The organicsolvents were evaporated and the resulting residue was cooled in an icebath and acidified with 2M H₃PO₄. The mixture was extracted with EtOAcand the combined organic layers were dried over MgSO4, filtered andevaporated to give the crude product, which was used without furtherpurification. LC-MS; M+1=414.

d. tert-Butyl6-benzyloxy-1-(hydroxymethyl)-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

To a solution of6-benzyloxy-2-tert-butoxycarbonyl-7-methoxy-3,4-dihydro-1H-isoquinoline-1-carboxylicacid (4.0 g, 9.67 mmol) in THF (10 mL) at 0° C. was added Borane-THFcomplex (19.2 mL, 19.2 mmol, 1M). The reaction mixture was stirred at rtfor 4 h. The reaction was quenched with water, extracted with EtOAc. Thecombined organic layer was washed with brine, dried (MgSO₄), andconcentrated. The crude product was obtained as colorless oil and usedin the next step without further purification. LC-MS; M+1=400.

e. tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfanylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate^(g)

To a stirred solution of tert-butyl6-benzyloxy-1-(hydroxymethyl)-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate(3.0 g, 7.5 mmol), phenyl-1H-tetrazole-5-thiol (1.6 g, 9.0 mmol), andtriphenylphosphine (2.36 g, 9.0 mmol) in THF (30 mL) was addeddiisopropyl azodicarboxylate (1.7 mL, 9.0 mol, 2.2 M solution in hexane)dropwise at 0° C. The solution was allowed to stir at 0° C. for anadditional 30 min and allowed to warm to room temperature overnight. Thereaction mixture was concentrated in vacuo to give a residue which waspurified by flash column chromatography (20%-30% EtOAc in hexane) togive the correct product. LC-MS; M+1=560.

f. tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate

tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfanylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(14.0 g, 25.03 mmol) was dissolved in a mixture of THF (50 mL), EtOH(100 mL) and DMF (50 mL) and cooled to 0° C. A solution of ammoniumparamolybdate tetrahydrate (12.6 g, 10.2 mmol) and 30% hydrogen peroxide(28 mL, 302.4 mmol) at 0° C. was added dropwise over 30 minutes. Thereaction mixture was allowed to warm to room temperature overnight,poured into saturated aqueous sodium thiosulfate, and extracted withethyl acetate three times. The combined organic layers were washed withwater and brine and dried over MgSO₄. The solvent was removed in vacuoand the residual product was purified by flash chromatography (30% EtOAcin hexane) to give the correct product. LC-MS; M+1=592.

REFERENCES

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IV. Methods of Inhibiting the Replication of a Virus

The compounds of the invention exhibit potency against viruses, andtherefore have the potential to inhibit the replication of viruses.

In a further aspect, the invention provides a method of inhibiting thereplication of a virus in an animal, comprising administering a compoundor a pharmaceutical formulation described herein to the animal, whereinthe animal is in need of treatment thereof, thereby inhibiting thereplication of the virus in an animal. In an exemplary embodiment, thevirus is a member of the retroviridae family. In an exemplaryembodiment, the virus is a member of the orthoretroviridae subfamily. Inan exemplary embodiment, the virus is a lentivirus. In an exemplaryembodiment, the virus is human immunodeficiency virus (HIV). In anexemplary embodiment, the virus is HIV-1. In an exemplary embodiment,the virus is HIV-2. In an exemplary embodiment, the compound isdescribed herein, or a salt, prodrug, hydrate or solvate thereof, or acombination thereof. In an exemplary embodiment, the invention providesa compound described herein, or a salt, hydrate or solvate thereof. Inan exemplary embodiment, the invention provides a compound describedherein, or a prodrug thereof. In an exemplary embodiment, the inventionprovides a compound described herein, or a salt thereof. In anotherexemplary embodiment, the compound of the invention is a compounddescribed herein, or a pharmaceutically acceptable salt thereof. Inanother exemplary embodiment, the compound is described by a formulalisted herein, or a pharmaceutically acceptable salt thereof. In anexemplary embodiment, the compound is part of a pharmaceuticalformulation described herein. In another exemplary embodiment, thecontacting occurs under conditions which permit entry of the compoundinto the organism. Such conditions are known to one skilled in the artand specific conditions are set forth in the Examples appended hereto.

In another aspect, the microorganism is inside, or on the surface of ananimal. In an exemplary embodiment, the animal is selected from thegroup consisting of human, cattle, deer, reindeer, goat, honey bee, pig,sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel,yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl,pigeon, swan, and turkey. In another exemplary embodiment, the animal isa human.

In an exemplary embodiment, the viral replication is inhibited throughoral administration of the compound of the invention. In an exemplaryembodiment, the viral replication is inhibited through intravenousadministration of the compound of the invention. In an exemplaryembodiment, the viral replication is inhibited through topicaladministration of the compound of the invention. In an exemplaryembodiment, the viral replication is inhibited through intraperitonealadministration of the compound of the invention. In an exemplaryembodiment, the compound is administered in a topically effectiveamount. In an exemplary embodiment, the pharmaceutical formulation isadministered in an orally effective amount.

V. Methods of Treating and/or Preventing Disease

The compounds of the invention exhibit potency against a virus, andtherefore have the potential to achieve therapeutic efficacy in theanimals described herein.

In another aspect, the invention provides a method of treating adisease. The method includes administering to the animal atherapeutically effective amount of the compound of the invention,sufficient to treat and/or prevent the disease. In an exemplaryembodiment, the compound of the invention can be used in human orveterinary medical therapy, particularly in the treatment ofviral-associated disease. In an exemplary embodiment, the compound ofthe invention can be used in human or veterinary medical therapy,particularly in the treatment or prophylaxis of lentivirus-associateddisease. In an exemplary embodiment, the disease is associated with ahuman immunodeficiency virus. In an exemplary embodiment, the disease isassociated with HIV-1. In an exemplary embodiment, the disease isassociated with HIV-2. In an exemplary embodiment, the disease is AIDS.In an exemplary embodiment, the compound is described herein, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. In anexemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or aprodrug thereof. In an exemplary embodiment, the invention provides acompound described herein, or a salt thereof. In another exemplaryembodiment, the compound of the invention is a compound describedherein, or a pharmaceutically acceptable salt thereof. In anotherexemplary embodiment, the compound is described by a formula listedherein, or a pharmaceutically acceptable salt thereof. In an exemplaryembodiment, the compound is part of a pharmaceutical formulationdescribed herein. In another exemplary embodiment, the contacting occursunder conditions which permit entry of the compound into the organism.Such conditions are known to one skilled in the art and specificconditions are set forth in the Examples appended hereto.

In another exemplary embodiment, the animal is selected from the groupconsisting of human, cattle, deer, reindeer, goat, honey bee, pig,sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel,yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl,pigeon, swan, and turkey. In another exemplary embodiment, the animal isa human. In another exemplary embodiment, the animal is a mouse. Inanother exemplary embodiment, the animal is selected from the groupconsisting of a human, cattle, goat, pig, sheep, horse, cow, bull, dog,guinea pig, gerbil, rabbit, cat, chicken and turkey. In anotherexemplary embodiment, the animal is a human. In another exemplaryembodiment, the animal is cattle. In another exemplary embodiment, theanimal is a cow. In another exemplary embodiment, the animal is a bull.

In an exemplary embodiment, the disease is treated through oraladministration of the compound of the invention. In an exemplaryembodiment, the disease is treated through intravenous administration ofthe compound of the invention. In an exemplary embodiment, the diseaseis treated through topical administration of the compound of theinvention. In an exemplary embodiment, the disease is treated throughintraperitoneal administration of the compound of the invention. In anexemplary embodiment, the compound is administered in a topicallyeffective amount. In an exemplary embodiment, the pharmaceuticalformulation is administered in an orally effective amount.

In an exemplary embodiment, the invention provides a method of treatingAIDS by administering a therapeutically effective amount of a compoundof the invention.

VI. Pharmaceutical Formulations

In another aspect, the invention is a pharmaceutical formulation whichincludes: (a) a pharmaceutically acceptable excipient; and (b) acompound of the invention. In another aspect, the pharmaceuticalformulation includes: (a) a pharmaceutically acceptable excipient; and(b) a compound according to a formula described herein. In anotheraspect, the pharmaceutical formulation includes: (a) a pharmaceuticallyacceptable excipient; and (b) a compound described herein, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. Inanother aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a compound describedherein, or a salt, hydrate or solvate thereof, or a combination thereof.In another aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a compound describedherein, or a salt, hydrate or solvate thereof. In another aspect, thepharmaceutical formulation includes: (a) a pharmaceutically acceptableexcipient; and (b) a salt of a compound described herein. In anexemplary embodiment, the salt is a pharmaceutically acceptable salt. Inanother aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a prodrug of a compounddescribed herein. In another aspect, the pharmaceutical formulationincludes: (a) a pharmaceutically acceptable excipient; and (b) acompound described herein. In an exemplary embodiment, thepharmaceutical formulation is a unit dosage form. In an exemplaryembodiment, the pharmaceutical formulation is a single unit dosage form.

The pharmaceutical formulations of the invention can take a variety offorms adapted to the chosen route of administration. Those skilled inthe art will recognize various synthetic methodologies that may beemployed to prepare non-toxic pharmaceutical formulations incorporatingthe compounds described herein. Those skilled in the art will recognizea wide variety of non-toxic pharmaceutically acceptable solvents thatmay be used to prepare solvates of the compounds of the invention, suchas water, ethanol, propylene glycol, mineral oil, vegetable oil anddimethylsulfoxide (DMSO).

The pharmaceutical formulation of the invention may be administeredorally, topically, intraperitoneally, parenterally, by inhalation orspray or rectally in unit dosage forms containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. It isfurther understood that the best method of administration may be acombination of methods. Oral administration in the form of a pill,capsule, elixir, syrup, lozenge, troche, or the like is particularlypreferred. The term parenteral as used herein includes subcutaneousinjections, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intrathecal injection or like injection orinfusion techniques. In an exemplary embodiment, the pharmaceuticalformulation is administered orally. In an exemplary embodiment, thepharmaceutical formulation is administered intravenously. In anexemplary embodiment, the pharmaceutical formulation is administeredintramuscularly. In an exemplary embodiment, the pharmaceuticalformulation is administered subcutaneously. In an exemplary embodiment,the pharmaceutical formulation is administered in an orally effectivedose.

The pharmaceutical formulations containing compounds of the inventionare preferably in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known in the art for the manufacture of pharmaceuticalformulations, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;and dispersing or wetting agents, which may be a naturally-occurringphosphatide, for example, lecithin, or condensation products of analkylene oxide with fatty acids, for example polyoxyethylene stearate,or condensation products of ethylene oxide with long chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol such as polyoxyethylene sorbitol monooleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one ormore coloring agents, one or more flavoring agents, and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical formulations of the invention may also be in the form ofoil-in-water emulsions and water-in-oil emulsions. The oily phase may bea vegetable oil, for example olive oil or arachis oil, or a mineral oil,for example liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally-occurring gums, for example gum acacia or gumtragacanth; naturally-occurring phosphatides, for example soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol; anhydrides, for example sorbitan monooleate; and condensationproducts of the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents. The pharmaceutical formulations may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents, which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The composition of the invention may also be administered in the form ofsuppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Alternatively, the compositions can be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

For administration to non-human animals, the composition containing thetherapeutic compound may be added to the animal's feed or drinkingwater. Also, it will be convenient to formulate animal feed and drinkingwater products so that the animal takes in an appropriate quantity ofthe compound in its diet. It will further be convenient to present thecompound in a composition as a premix for addition to the feed ordrinking water. The composition can also be added as a food or drinksupplement for humans.

Dosage levels of the order of from about 1 mg to about 250 mg perkilogram of body weight per day and more preferably from about 5 mg toabout 150 mg per kilogram of body weight per day, and more preferablyfrom about 25 mg to about 150 mg per kilogram of body weight per day,are useful in the treatment of the above-indicated conditions. Theamount of active ingredient that may be combined with the carriermaterials to produce a unit dosage form will vary depending upon thecondition being treated and the particular mode of administration. Unitdosage forms will generally contain between from about 1 mg to about5000 mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily or less is preferred. It will beunderstood, however, that the specific dose level for any particularanimal (such as a human) will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

In an exemplary embodiment, the unit dosage form contains from about 1mg to about 7000 mg of a compound of the invention. In an exemplaryembodiment, the unit dosage form contains from about 1 mg to about 5000mg of an active ingredient. In an exemplary embodiment, the unit dosageform contains from about 100 mg to about 2000 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 200 mg to about 1000 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 500 mg toabout 800 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 1 mg to about 100 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 10 mg to about 100 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 50 mg to about 100 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 25 mg toabout 75 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 40 mg to about 60 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 75 mg to about 200 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 1 mg to about 5 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 10 mg toabout 25 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 50 mg to about 350 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 200 mg to about 400 mg of a compound of theinvention.

In an exemplary embodiment, the daily dosage contains from about 1 mg toabout 800 mg of a compound of the invention. In an exemplary embodiment,the daily dosage contains from about 1 mg to about 500 mg of an activeingredient. In an exemplary embodiment, the daily dosage contains fromabout 100 mg to about 800 mg of a compound of the invention. In anexemplary embodiment, the daily dosage contains from about 200 mg toabout 500 mg of a compound of the invention. In an exemplary embodiment,the daily dosage contains from about 500 mg to about 800 mg of acompound of the invention. In an exemplary embodiment, the daily dosagecontains from about 1 mg to about 100 mg of a compound of the invention.In an exemplary embodiment, the daily dosage contains from about 10 mgto about 100 mg of a compound of the invention. In an exemplaryembodiment, the daily dosage contains from about 50 mg to about 100 mgof a compound of the invention. In an exemplary embodiment, the dailydosage contains from about 75 mg to about 200 mg of a compound of theinvention. In an exemplary embodiment, the daily dosage contains fromabout 1 mg to about 5 mg of a compound of the invention. In an exemplaryembodiment, the daily dosage contains from about 10 mg to about 25 mg ofa compound of the invention. In an exemplary embodiment, the dailydosage contains from about 50 mg to about 350 mg of a compound of theinvention. In an exemplary embodiment, the daily dosage contains fromabout 200 mg to about 400 mg of a compound of the invention.

Preferred compounds of the invention will have desirable pharmacologicalproperties that include, but are not limited to, bioavailability, lowtoxicity, low serum protein binding and desirable in vitro and in vivohalf-lives. Penetration of the blood brain barrier for compounds used totreat CNS disorders is necessary, while low brain levels of compoundsused to treat peripheral disorders are often preferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of laboratory animalsthat receive the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcova, et al. (Journal ofChromatography B (1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lives of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

The amount of the composition required for use in treatment will varynot only with the particular compound selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the animal (such as a human) and will ultimately be atthe discretion of the attendant physician or clinician.

VI. a) Testing

Preferred compounds for use in the pharmaceutical formulations describedherein will have certain pharmacological properties. Such propertiesinclude, but are not limited to, low toxicity, low serum protein bindingand desirable in vitro and in vivo half-lives. Assays may be used topredict these desirable pharmacological properties. Assays used topredict bioavailability include transport across human intestinal cellmonolayers, including Caco-2 cell monolayers. Serum protein binding maybe predicted from albumin binding assays. Such assays are described in areview by Oravcova et al. (1996, J. Chromat. B677: 1-27). Compoundhalf-life is inversely proportional to the frequency of dosage of acompound. In vitro half-lives of compounds may be predicted from assaysof microsomal half-life as described by Kuhnz and Gleschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio between LD₅₀and ED₅₀. Compounds that exhibit high therapeutic indices are preferred.The data obtained from these cell culture assays and animal studies canbe used in formulating a range of dosages for use in humans or animals.The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage can vary within this range depending upon the unitdosage form employed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the human's condition. (See, e.g. Finglet al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1, p.1).

VI. b) Administration

For any compound used in the method of the invention, thetherapeutically effective dose can be estimated initially from cellculture assays, as disclosed herein. For example, a dose can beformulated in animal models to achieve a circulating concentration rangethat includes the EC₅₀ (effective dose for 50% increase) as determinedin cell culture, i.e., the concentration of the test compound whichachieves a half-maximal inhibition of viral cell growth. Suchinformation can be used to more accurately determine useful doses inhumans or animals.

In general, the compounds prepared by the methods, and from theintermediates, described herein will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. It will beunderstood, however, that the specific dose level for any particularanimal (such as a human) will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination, the severity ofthe particular disease undergoing therapy and the judgment of theprescribing physician. The drug can be administered from once or twice aday, or up to 3 or 4 times a day.

Dosage amount and interval can be adjusted individually to provideplasma levels of the active moiety that are sufficient to maintain viralgrowth inhibitory effects. Usual animal (such as a human) dosages forsystemic administration range from 0.1 to 1000 mg/day, preferably, 1-500mg/day, more preferably 10-200 mg/day, even more preferably 100-200mg/day. Stated in terms of animal (such as a human) body surface areas,usual dosages range from 50-91 mg/m²/day.

The amount of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-10 wt %of the drug based on the total formulation, with the balance being oneor more suitable pharmaceutical excipients. Preferably, the compound ispresent at a level of about 0.1-3.0 wt %, more preferably, about 1.0 wt%.

Exemplary embodiments are summarized herein below.

In an exemplary embodiment, the invention provides a pharmaceuticalformulation comprising: a) the compound according to any of the aboveparagraphs, or a pharmaceutically acceptable salt thereof; and b) apharmaceutically acceptable excipient.

In an exemplary embodiment, the invention provides a method ofinhibiting the replication of a virus in an animal, comprising:administering a compound or a pharmaceutical formulation of a precedingclaim to the animal, wherein the animal is in need of treatment thereof,thereby inhibiting the replication of the virus in an animal.

In an exemplary embodiment, according to any of the above paragraphs,wherein the virus is a member of the Orthoretroviridae family.

In an exemplary embodiment, according to any of the above paragraphs,wherein the virus is HIV.

In an exemplary embodiment, the invention provides a method of treatinga disease in an animal, comprising: a) administering a compound or apharmaceutical formulation described herein to the animal, wherein theanimal is in need of treatment thereof, thereby treating the disease inthe animal.

In an exemplary embodiment, according to any of the above paragraphs,the disease is AIDS.

In an exemplary embodiment, according to any of the above paragraphs,the animal is a human.

In an exemplary embodiment, according to any of the above paragraphs,the invention is a use of a compound of the invention or apharmaceutical formulation of the invention in the manufacture of amedicament for the treatment of a viral infection.

The invention is further illustrated by the Examples that follow. TheExamples are not intended to define or limit the scope of the invention.

EXAMPLES

The following Examples illustrate the synthesis of representativecompounds used in the invention and the following Reference Examplesillustrate the synthesis of intermediates in their preparation. Theseexamples are not intended, nor are they to be construed, as limiting thescope of the invention. It will be clear that the invention may bepracticed otherwise than as particularly described herein. Numerousmodifications and variations of the invention are possible in view ofthe teachings herein and, therefore, are within the scope of theinvention.

All temperatures are given in degrees Centigrade. Room temperature means20 to 25° C. Reagents were purchased from commercial sources or preparedfollowing standard literature procedures. Unless otherwise noted,reactions were carried out under a positive pressure of nitrogen.Reaction vessels were sealed with either rubber septa or Teflon screwcaps. Nitrogen was introduced through Tygon tubing, fitted with a largebore syringe needle. Concentration under vacuum refers to the removal ofsolvent on a Büchi Rotary Evaporator.

Analytical HPLC was performed using a Supelco discovery C₁₈15 cm×4.6mm/5 μm column coupled with an Agilent 1050 series VWD UV detector at210 nm. Conditions: Solvent A: H₂O/1% acetonitrile/0.1% HCO₂H; SolventB: methanol.

Proton magnetic resonance (¹H NMR) spectra were recorded on a VarianINOVA NMR spectrometer [400 MHz (¹H) or 500 MHz (¹H)] or Varian 400-MR[400 MHz (1H)]. All spectra were determined in the solvents indicated.Although chemical shifts are reported in ppm downfield oftetramethylsilane, they are referenced to the residual proton peak ofthe respective solvent peak for ¹H-1 NMR. Interproton coupling constantsare reported in Hertz (Hz).

LCMS spectra were obtained using a ThermoFinnigan AQA MS ESI instrumentutilizing a Phenomenex Aqua 5 micron C₁₈125 Å 50×4.60 mm column. Thespray setting for the MS probe was at 350 μL/min with a cone voltage at25 mV and a probe temperature at 450° C. The spectra were recorded usingELS and UV (254 nm) detection. Alternatively, LCMS spectra were obtainedusing an Agilent 1200SL HPLC equipped with a 6130 mass spectrometer orAgilent 1200 series with a 6140 mass spectrometer operating withelectrospray ionization.

Silica gel chromatography was carried out on either a Teledyne ISCOCombiFlash Companion or Companion Rf Flash Chromatography System with avariable flow rate from 5-100 mL/min. The columns used were TeledyneISCO RediSep Disposable Flash Columns (4, 12, 40, 80, or 120 g prepackedsilica gel), which were run with a maximum capacity of 1 g crude sampleper 10 g silica gel. Samples were preloaded on Celite in Analogix SampleLoading Cartridges with frits (1/in, 1/out). The eluent was 0-100% EtOAcin heptane or 0-10% MeOH in CH₂Cl₂ as a linear gradient over the lengthof the run (14-20 minutes). Peaks were detected by variable wavelengthUV absorption (200-360 nm). The resulting fractions were analyzed,combined as appropriate, and evaporated under reduced pressure toprovide purified material.

EXAMPLES Example A1-[2-(3,4-Dimethoxyphenyl)ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

To the solution of 3,4-dimethoxyphenethyl bromide (1.78 g, 7.28 mmol) inanhydrous THF (30 mL), under argon, at −78° C. was added MeLi (6 mL,1.6M in diethyl ether, 9.6 mmol), the resulting mixture was stirred for1 hr. A solution of t-BuLi (9 mL, 1.7M in pentane, 15.30 mmol), stirredat −78° C. for another 1 hr, then the solution of commercially available6,7-dimethoxy-3,4-dihydroisoquinoline (1.67 g, 8.73 mmol) in THF (20 mL)was added with the aid of a syringe. After all the addition, theresulting mixture was stirred at −78° C. for 3 hrs, quenched with satd.aqueous NH₄Cl solution and gradually allowed to warm to room temperatureand extracted with EtOAc. The organic layer was washed with brine, dried(Na₂SO₄), filtered, concentrated and purified with flash chromatographyusing MeOH (NH₃)/CHCl₃ gradient to afford the titled compound. M+H=358.

Example B[6-Benzyloxy-1-[(E)-2-(3-benzyloxy-4-methoxy-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl-methanone

To the solution of(E)-6-(benzyloxy)-1-(3-(benzyloxy)-4-methoxystyryl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline(81.4 mg, 0.13 mmol) in anhydrous DMF (2 mL), was addedpyrazine-2-carboxylic acid (81 mg, 0.65 mmol), HATU (250 mg, 0.66 mmol)and DIPEA (1 mL). The resulting solution was stirred at room temperatureovernight. After the usual workup, the crude obtained was purified onthe Shimadzu HPLC system to afford the TFA salt. M+H (Neutral)=614.

Example C1-[(E)-2-(5-Benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

(E)-1-(Benzyloxy)-5-(2-bromovinyl)-2-methoxy-4-methylbenzene (334 mg,1.0 mmol) was dissolved in dry Et₂O (15 mL) and cooled to −78° C. Asolution of t-BuLi (1.3 mL mL, 2.2 mmol, 1.7M in pentane) was addeddropwise and the resulting solution was stirred at −78° C. for 1 hourbefore a solution of 6,7-dimethoxy-3,4-dihydroisoquinoline (191 mg, 1.0mmol), in THF (3 mL) was added dropwise. The resulting mixture wasstirred for 2 hours at −78° C. and then quenched with sat. aqueous NH₄Clsolution. The mixture was extracted with EtOAc and the combined organiclayers were dried over MgSO₄, filtered and evaporated to dryness. Theresidue obtained was purified by flash silica gel chromatography toafford the titled compound. LCMS: M+1=425.6.

Example D7-Benzyloxy-1-[(E)-2-(4-benzyloxy-3-methoxy-phenyl)vinyl]-2-butyl-6-methoxy-3,4-dihydro-1H-isoquinoline

To the solution of(E)-7-(benzyloxy)-1-(4-(benzyloxy)-3-methoxystyryl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline(86 mg, 0.17 mmol) in DMF (3 mL) was added KH (15 mg, 0.37 mmol),followed by 1-iodobutane (0.100 mL, 0.88 mmol). The resulting solutionwas stirred at room temperature overnight. The reaction mixture wasdiluted with EtOAc, washed with brine, dried (Na₂SO₄), filtered,concentrated and purified with flash chromatography using hexanes/EtOAcgradient to afford the titled compound. M+H=564.

Example E6-Benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-2-methyl-3,4-dihydro-1H-isoquinoline

A mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[50 mg (0.1 mmol)] and 50 μl of 38% formalin with 500 μl of MeOH wasstirred at room temperature for 1 h then treated with 40 mg of NaBH₄.After stirring 12 h at room temperature the mixture was diluted with 10mL of DCM and washed with water. The DCM layer was dried (Na₂SO₄) thenfiltered and the filtrate rotary evaporated to dryness. Yield=13.4 mg(25% yield) via prep chrom. MS (m/z): 536 [M+H]

Example F(6-Amino-2-pyridyl)-[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]methanone

To a mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[50 mg (0.097 mmol)], 6-aminopyridine-2-carboxylic acid [13.8 mg (0.1mmol)], DIEA [50 uL (0.3 mmol)] and 1 mL of DMF was added HATU [47.5 mg(0.125 mmol)]. The reaction was stirred at rt for 1 h and then dilutedwith 20 mL of EtOAc and washed 2× with sat NaCl. The EtOAc layer wasdried (Na₂SO₄) and the solvent removed. Yield=35 mg (57%) via prep.chrom. MS (m/z): 642 [M+H]

Example G6-Benzyloxy-1-[(E)-2-(3-benzyloxy-4-methoxy-phenyl)vinyl]-2-butyl-7-methoxy-3,4-dihydro-1H-isoquinoline

To the solution of(E)-6-(benzyloxy)-1-(3-(benzyloxy)-4-methoxystyryl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline(0.2841 g, 0.56 mmol), in DMF (5 mL) was added KH (25 mg, 0.62 mmol),followed by 1-iodobutane (0.32 mL, 2.81 mmol). The resulting mixture wasstirred at room temperature overnight, After workup, the crude obtainedwas purified on the Shimadzu HPLC system to afford the TFA salt. M+H(Neutral)=564.

Example H[6-Benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl-methanone

To a mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[50 mg (0.097 mmol)], Pyrazine carboxylic acid [12.4 mg (0.1 mmol)],DIEA [50 ul (0.3 mmol)] and 1 mL of DMF was added HATU [47.5 mg (0.125mmol)]. The reaction was stirred at rt for 1 h and then diluted with 20mL of EtOAc and washed 2× with sat NaCl. The EtOAc layer was dried(Na₂SO₄) and the solvent removed. Yield=51.2 mg (84%) via prep chrom. MS(m/z): 628 [M+H]

Example I Methyl6-benzyloxy-1-[(E)-2-(4,5-dimethoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

A mixture of6-benzyloxy-1-[(E)-2-(4,5-dimethoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[44.5 mg (0.1 mmol)] and 2 mL of DCM with DIEA [26 uL (0.15 mmol)] wastreated with Methyl chloroformate [14 ul (0.12 mmol)] and stirred atroom temperature for 1 h. The mixture was diluted with 10 mL of DCM andwashed with water. The DCM layer was dried (Na₂SO₄) then filtered andthe filtrate rotary evaporated to dryness. Yield=50 mg (99% yield) MS(m/z): 504 [M+H]

Example J6-Benzyloxy-1-[(E)-2-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

4-tert-Butyl-2-methoxy-phenol^(a)

A mixture of 4-t-butyl-2-bromophenol [5. g (0.0218 mol)], Copper(II)chloride [1.5 g (0.0112 mol)], NaOMe [12 g (0.218 mol) in 150 mL of DMFwas refluxed for 4.5 h, filtered and the solvent removed via rotaryevaporation. The residue was diluted with water and treated with conc.HCl until neutral. The mixture was then extracted with DCM, dried(Na₂SO₄) and the solvent removed affording the desired4-tert-butyl-2-methoxy-phenol. Yield=3.1 g (79% after flashchromatography with DCM) MS (m/z): 181 [M+H]

Synthesis of 5-bromo-4-tert-butyl-2-methoxy-phenol^(b)

To a solution of 4-tert-butyl-2-methoxy-phenol [3.1 g (0.0172 mol)] inCCl₄ (62 mL) was added drop wise a solution of Br₂ [0.9 mL (0.0174 mol)]in CCl₄ (31 mL) at 100° C. Upon completion the reaction was washed withwater, dried (Na₂SO₄) and the solvent removed affording5-bromo-4-tert-butyl-2-methoxy-phenol. Yield=4 g (90% used withoutfurther purification) MS (m/z): 259 [M+H].

1-Benzyloxy-5-bromo-4-tert-butyl-2-methoxy-benzene^(c)

A mixture of 5-bromo-4-tert-butyl-2-methoxy-phenol [4 g (0.01555 mol)],Benzyl bromide [5.3 g (0.031 mol)], K₂CO₃ [4.28 g (0.031 mol) in ACN (31mL) was refluxed for 18 h, cooled and the solvent removed via rotaryevaporation. The residue was diluted with water and extracted withEtOAc. The extract was then dried (MgSO₄) and the solvent removedaffording the desired1-benzyloxy-5-bromo-4-tert-butyl-2-methoxy-benzene. Yield=4.5 g (83%after flash chromatography with 10% EtOAc/Hexane) MS (m/z): 349 [M+H]

5-(Benzyloxy)-2-tert-butyl-4-methoxybenzaldehyde

To a solution of 1-benzyloxy-5-bromo-4-tert-butyl-2-methoxy-benzene [4.5g (0.0129 mol)] in THF (15 mL) was added, at −78° C., 1.7M t-Butyllithium [8.8 mL (0.014 mol)]. The reaction mixture was then stirred at−780 C for 40 min and then treated with DMF [5 mL (0.0645 mol)]. Themixture was then allowed to slowly come to room temperature overnightand was then quenched with sat NH₄Cl, extracted with Et₂O. The extractwas dried (MgSO₄) and the solvent removed affording5-benzyloxy-2-tert-butyl-4-methoxy-benzaldehyde. Yield=0.52 g (13% usedwithout further purification) MS (m/z): 299 [M+H]

(E)-3-(5-Benzyloxy-2-tert-butyl-4-methoxy-phenyl)prop-2-enoic acid

A mixture of 5-benzyloxy-2-tert-butyl-4-methoxy-benzaldehyde [0.520 g(0.0017 mol)], malonic acid [0.354 g (0.0034 mol)], pyridine (3 mL) andpiperidine (0.1 mL) was stirred at 80° C. for 1 h followed by stirringfor 3 h at 115° C. The reaction was then poured into water (20 mL) andacidified with conc. HCl. The resulting white ppt. was filtered andvacuum dried affording the desired(E)-3-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)prop-2-enoic acid.Yield=0.6 g (quant) MS (m/z): 341 [M+H]

(E)-3-(5-Benzyloxy-2-tert-butyl-4-methoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]prop-2-enamide

To a mixture of(E)-3-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)prop-2-enoic acid [163mg (0.5 mmol)], 2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [129 mg (0.5mmol)], DMF (2 mL) and DIEA [0.250 mL (1.4 mmol)] was added HATU [238 mg(0.62 mmol)]. The reaction mix was stirred at room temperature 2 h thendiluted with 20 mL of EtOAc and washed 2× with sat. NaCl aq. The EtOAclayer was dried (MgSO₄) and the solvent removed affording(E)-3-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl] prop-2-enamide. Yield=225 mg (78% after flash with 10% MeOH/DCM)MS (m/z): 580 [M+H]

6-Benzyloxy-1-[(E)-2-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)vinyl]-7-methoxy-3,4-dihydroisoquinoline

To a solution of(E)-3-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]prop-2-enamide[225 mg (0.39 mmol)] in ACN (9 mL) was added, under reflux, POCl₃ [300ul (3.21 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 mL ofchloroform and was then treated with 20 mL of 2N KOH and 50 mL of Et₂O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na₂SO₄) and thesolvent removed. Yield=205 mg crude: A 50 mg fraction was removed andpurified via reverse phase preparatory chromatography affording 15 mg(23% yield) MS (m/z): 562 [M+H]

6-Benzyloxy-1-[(E)-2-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

The crude6-benzyloxy-1-[(E)-2-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)vinyl]-7-methoxy-3,4-dihydroisoquinolinefrom the previous reaction (155 mg) was the dissolved into 8 mL of dryEtOH and then treated with NaBH₄ [12 mg (0.32 mmol)]. The mixture wasstirred for 1 h at room temperature and the resulting solid wascarefully filtered off and dried. The solid was triturated with 50/50ACN/water, filtered and vacuum dried. Yield=50 mg (11% overall) MS(m/z): 564 [M+H]

Example K(2-Amino-3-pyridyl)-[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]methanone

To a mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[50 mg (0.097 mmol)], 2-aminopyridine-3-carboxylic acid [13.8 mg (0.1mmol)], DIEA [50 ul (0.3 mmol)] and 1 mL of DMF was added HATU [47.5 mg(0.125 mmol)]. The reaction was stirred at rt for 1 h and then dilutedwith 20 mL of EtOAc and washed 2× with sat NaCl. The EtOAc layer wasdried (Na₂SO₄) and the solvent removed. Yield=24 mg (39%) via prep chromMS (m/z): 642 [M+H]

Example L Methyl6-benzyloxy-1-[(E)-2-(3-benzyloxy-4-methoxy-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

To the solution of(E)-6-(benzyloxy)-1-(3-(benzyloxy)-4-methoxystyryl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline(51.4 mg, 0.083 mmol) in anhydrous 1,2-dichloroethane (3 mL) was addedDIPEA (0.5 mL) followed by methyl chloroformate (33 micromL, 0.43 mmol).The resulting solution was stirred at room temperature overnight. It wasconcentrated to dryness and purified on the Shimadzu HPLC system toafford the TFA salt. M+H (Neutral)=566.

Example M[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-(2-pyridyl)methanone

To a mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[50 mg (0.097 mmol)], Picolinic acid [12.4 mg (0.1 mmol)], DIEA [50 ul(0.3 mmol)] & 1 mL of DMF was added HATU [47.5 mg (0.125 mmol)]. Thereaction was stirred at rt for 1 h and then diluted with 20 mL of EtOAcand washed 2× with sat NaCl. The EtOAc layer was dried (Na₂SO₄) and thesolvent removed. Yield=42 mg (58%) via prep chrom. MS (m/z): 627 [M+H]

Example N(2-amino-4-pyridyl)-[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]methanone

To a mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[50 mg (0.097 mmol)], 2-aminopyridine-4-carboxylic acid [13.8 mg (0.1mmol)], DIEA [50 ul (0.3 mmol)] & 1 mL of DMF was added HATU [47.5 mg(0.125 mmol)]. The reaction was stirred at rt for 1 h and then dilutedwith 20 mL of EtOAc and washed 2× with sat NaCl. The EtOAc layer wasdried (Na₂SO₄) and the solvent removed. Yield=28 mg (46%) via prepchrom. MS (m/z): 642 [M+H]

Example 06-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-N-tert-butyl-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxamide

A mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[50 mg (0.1 mmol)] and 2 mL of DCM was treated with t-Butylisocyanate[14 μl (0.12 mmol)] and stirred at room temperature for 1 h. The mixturewas diluted with 10 mL of DCM and washed with water. The DCM layer wasdried (Na₂SO₄) then filtered and the filtrate rotary evaporated todryness. Yield=13 mg (21% yield) via prep chrom. MS (m/z): 621 [M+H]

Example P(6-amino-3-pyridyl)-[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]methanone

To a mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[50 mg (0.097 mmol)], 6-aminopyridine-3-carboxylic acid [13.8 mg (0.1mmol)], DIEA [50 ul (0.3 mmol)] and 1 mL of DMF was added HATU [47.5 mg(0.125 mmol)]. The reaction was stirred at rt for 1 h and then dilutedwith 20 mL of EtOAc and washed 2× with sat NaCl. The EtOAc layer wasdried (Na₂SO₄) and the solvent removed. Yield=30 mg (49%) via prepchrom. MS (m/z): 642 [M+H]

Example Q6-benzyloxy-1-[2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)ethyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

A mixture of6-benzyloxy-1-[(E)-2-(3-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[100 mg (0.1919 mmol)] and 10 mg of PtO₂ in 10 mL of 50/50 THF/EtOH wasrapidly stirred, evacuated and filled with H₂ gas 3×. The reaction mixwas then stirred under positive H₂ pressure using a balloon for 2 h,then filtered and the filtrate rotary evaporated to dryness.

Yield=44.6 mg (45% yield) via prep chrom. MS (m/z): 524 [M+H]

Example R6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxamide

A mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[50 mg (0.1 mmol)] and 2 mL of DCM was treated with TMS-Isocyanate [13mg (0.11 mmol)] and stirred at room temperature for 1 h. The mixture wasdiluted with 10 mL of DCM and washed with water. The DCM layer was dried(Na₂SO₄) then filtered and the filtrate rotary evaporated to dryness.Yield=38.1 mg (70% yield) Triturated from ACN/Water. MS (m/z): 565 [M+H]

Example S7-benzyloxy-1-[(E)-2-(4-benzyloxy-3-methoxy-phenyl)vinyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-1-(Benzyloxy)-2-methoxy-4-(2-nitrovinyl)benzene

4-Benzyloxy-3-methoxyphenethylamine was prepared according toSchrittweieser. J. H, et, J.O.C. 2011, 76, 6703-6714. A solution of4-(benzyloxy)-3-methoxybenzaldehyde (25 g, 103.2 mmol), nitromethane (18mL, 333.2 mmol) and NH₄OAc (20.23 g, 262.5 mmol) in AcOH (220 mL) wasrefluxed for 5 hr. After cooling it was poured into ice-water (300 mL),followed by addition CH₂Cl₂ (200 mL) stirred at room temperature untilthe phases were separated. The aqueous phase was extracted with theCH₂Cl₂ (3×100 mL). The combined organics were washed with water (200mL), saturated NaHCO₃ (200 mL), brine (200 mL), dried (Na₂SO₄), filteredand concentrated to afford a brownish solid which was recrystallizedfrom ethanol to afford the desired compound in 68% yield.

2-(4-(Benzyloxy)-3-methoxyphenyl)ethanamine

To a suspension of LiAlH₄ (8 g, 210 mmol) in anhydrous THF (120 mL)under argon was added dropwise a solution of the4-benzyloxy-3-methoxy-beta-nitrostyrene (11.51 g, 40.34 mmol) in THF (80mL) over 1 hr. After the addition, the resulting mixture was stirred andheated to reflux for 16 hr, then diluted with THF (100 mL), cooled (0°C.) ice-bath. To the vigorously stirred mixture was added water (8 mL),15% NaOH (8 mL) and water (24 mL). The ice-bath was removed, thestirring was continued for 1 hr at room temperature. The resultingsuspension was filtered through a celite pad washed with THF. Thecombined washings and filtrate were concentrated to dryness. The residueobtained was dissolved in 10% HCl (20 mL) washed with ether, basifiedand extracted with EtOAc (3×100 mL). The combined organics were washedwith water, brine, dried (K₂CO₃), filtered and concentrated to drynessto afford 8 g of 4-benzyloxy-3-methoxyphenethylamine as a yellowish oil.M+H=258.

(E)-3-(4-(Benzyloxy)-3-methoxyphenyl)acrylic acid

The (E)-3-(4-(benzyloxy)-3-methoxyphenyl)acrylic acid was prepared bythe Knoevenagel condensation reaction (Kaushik. M. et. al. J. ofMolecular Catalysis B; Enzymatic 82 (2912) 92-95. A mixture of4-(benzyloxy)-3-methoxybenzaldehyde (14.54 g, 60.02 mmol), malonic acid(12.5 g, 120 mmol), pyridine (40 mL) and piperidine (1 mL, 10.12 mmol)was stirred and heated to 85° C. for 1 hr and refluxed 115° C. for anadditional 5 hr. The mixture was poured into water and acidified withconc HCl. The precipitate was collected washed with cold water. Thewhite solid residue was dissolved in NaOH, diluted with water, acidifiedagain, the white solid precipitate was collected washed several timeswith water, and dried over P₂O₅ under high vacuum overnight.

(E)-N-(4-(Benzyloxy)-3-methoxyphenethyl)-3-(4-(benzyloxy)-3-methoxyphenyl)acrylamide

To the mixture of (E)-3-(4-benzyloxy)-3-methoxyphenyl)acrylic acid (5.16g, 18.15 mmol), 2-(4-(benzyloxy-3-methoxyphenyl)ethanamine (5.6 g, 21.76mmol), HATU (8.3 g, 21.83 mmol) in anhydrous DMF (100 mL) was addedDIPEA (16 mL, 91.85 mmol). The resulting mixture was stirred at roomtemperature for 2 hr, diluted with EtOAc (500 mL), washed sequentiallywith water, brine, dried (Na₂SO₄), filtered, concentrated and purifiedby flash chromatography using MeOH/CHCl₃ gradient to afford the titledcompound in 60% yield. M+H=524.

(E)-7-(Benzyloxy)-1-(4-(benzyloxy)-3-methoxystyryl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline

The mixture of(E)-N-(benzyloxy)-3-methoxyphenethyl)-3-(4-(benzyloxy)-3-methoxyphenyl)acrylamide(1.7 g, 3.25 mmol) and anhydrous acetonitrile (60 mL) was stirred andheated to reflux, POCl₃ (2.2 mL, 23.60 mmol) was added dropwise. Afterthe addition, the resulting reddish solution was stirred and heated toreflux for 1 hr, and concentrated to dryness. The residue was taken upEtOAc (100 mL), treated with 2M KOH solution (20 mL), stirred rapidlyfor 1 hr. The organic layer was washed with water, brine, dried overNa₂SO₄, filtered and concentrated to dryness. To the residue obtainedwas added NaBH4 (100 mg, 2.63 mmol), EtOH (35 mL) and stirred at roomtemperature for 1 hr. The excess reagent was destroyed by dropwiseaddition of 2M HCl, basified with 2M KOH and evaporated to dryness toremove EtOH. The residue obtained was partitioned between water andCHCl₃, the organic layer was washed with brine, dried (K₂CO₃), filtered,concentrated and purified by flash chromatography using MeOH (NH₃)/CHCl₃gradient to afford the titled compound. M+H=508.

Example T[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-(3-pyridyl)methanone

To a mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[50 mg (0.097 mmol)], Nicotinic acid [12.4 mg (0.1 mmol)], DIEA [50 ul(0.3 mmol)] & 1 mL of DMF was added HATU [47.5 mg (0.125 mmol)]. Thereaction was stirred at rt for 1 h and then diluted with 20 mL of EtOAcand washed 2× with sat NaCl. The EtOAc layer was dried (Na₂SO₄) and thesolvent removed. Yield=62 mg (86%) via prep chrom. MS (m/z): 627 [M+H]

Example U[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-(4-pyridyl)methanone

To a mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline)[25 mg (0.048 mmol)], Isonicotinic acid [9 mg (0.072 mmol)], DIEA [42 ul(0.24 mmol)] & 1 mL of DMF was added HATU [38 mg (0.1 mmol)]. Thereaction was stirred at rt for 1 h and then diluted with 20 mL of EtOAcand washed 2× with sat NaCl. The EtOAc layer was dried (Na₂SO₄) and thesolvent removed. Yield=11.5 mg (38%) via prep chrom. MS (m/z): 627 [M+H]

Example V6-benzyloxy-1-[(E)-2-(3-benzyloxy-4-methoxy-phenyl)vinyl]-7-methoxy-2-methyl-3,4-dihydro-1H-isoquinoline

A mixture of(E)-6-(benzyloxy)-1-(3-(benzyloxy)-4-methoxystyryl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline(0.4697 g, 0.93 mmol) and (0.4844 mL) of 38% formalin with EtOH (10 mL)was stirred at room temperature for 1 hr then treated with NaBH₄ (0.372g, 9.83 mmol) and stirred overnight. The mixture was diluted with DCM(50 mL), washed with brine, dried (Na₂SO₄), filtered, concentrated andpurified on the Shimadzu HPLC system to afford the TFA salt. M+H(Neutral)=522.

Example W6-benzyloxy-7-methoxy-1-[(E)-2-(o-tolyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-7-methoxy-1-(2-methylstyryl)-1,2,3,4-tetrahydroisoquinoline

Title compound was prepared analogously as Example X using(E)-3-o-tolylacrylic acid (0.4235 g, 2.61 mmol) and2-(3-(benzyloxy)-4-methoxyphenyl)ethanamine (0.7392 g, 2.87 mmol) viathe HATU coupling, the imine formation, and NaBH₄ reduction in EtOH/DCMmixture. M+H=386.

Example X6-benzyloxy-1-[(E)-2-(4-fluoro-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-N-(3-(Benzyloxy)-4-methoxyphenethyl)-3-(4-fluoro-2-methylphenyl)acrylamide

The amide was formed from the (E)-3-(4-fluoro-2-methylphenyl)acrylicacid (0.8 g, 4.88 mmol) and the amine (1.63 g, 6.33 mmol) by the HATUcoupling procedure.

(E)-6-(Benzyloxy)-1-(4-fluoro-2-methylstyryl)-7-methoxy-3,4-dihydroisoquinoline

The mixture of the amide (1.04 g, 2.48 mmol) in acetonitrile (30 mL) wasstirred and heated to reflux, POCl₃ (1.6 mL, 17.17 mmol) was addeddropwise, stirred for 1 hr and worked up as usual.

(E)-6-(Benzyloxy)-1-(4-fluoro-2-methylstyryl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

The crude imine obtained was treated with NaBH₄ (60 mg, 1.59 mmol) inEtOH (5 mL)/DCM 2 (mL), stirred at room temperature for 1 hr, the solidprecipitate was filtered off washed with 50/50 ACN/water and dried underhigh vacuum to afford the titled compound. M+H=404.

Example Y tert-butyl6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

To a mixture of6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline[100 mg (0.1919 mmol)] and Di-t-butyl dicarbonate [42 mg (0.1919 mmol)]in 5 mL of DCM was stirred at room temperature for 1 h then rotaryevaporated to dryness. Yield=25 mg (21% yield) via prep chrom. MS (m/z):622 [M+H].

Example Z6-benzyloxy-7-methoxy-1-[(E)-2-[4-methoxy-2-(trifluoromethyl)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-7-methoxy-1-(4-methoxy-2-(trifluoromethyl)styryl)-3,4-dihydroisoquinoline

To the mixture of (E)-3-(4-methoxy-2-(trifluoromethyl)phenyl)acrylicacid (1.36 g, 5.52 mmol) prepared from the aldehyde by the usualKnoevenagel condensation reaction (1.56 g, 6.06 mmol), HATU (2.30 g,6.06 mmol) in DMF (25 mL) was added DIPEA (4.8 mL, 27.56 mmol) andstirred at room temperature for 2 hr. After workup, the crude waspurified with flash chromatography using EtOAc/Hexanes gradient toafford the amide. The mixture of the amide (1.04 g, 2.14 mmol) andacetonitrile (25 mL) was stirred and heated to reflux, POCl₃ (1.4 mL,15.02 mmol) was added dropwise, stirred and heated to reflux for 1 hr.After the usual workup, ca 200 mg of the desired product was purified onthe Shimadzu HPLC to afford the TFA salt.

(E)-6-(Benzyloxy)-7-methoxy-1-(4-methoxy-2-(trifluoromethyl)styryl)-1,2,3,4-tetrahydroisoquinoline

The remaining crude was treated with NaBH₄ (51 mg, 1.35 mmol) in EtOH(25 mL) for 1 hr. After the usual workup it was purified with flashchromatography using MeOH (NH₃)/CHCl₃ gradient to afford the titledcompound. M+H=470.

Example AA6-benzyloxy-1-[(E)-2-(5-benzyloxy-2-ethyl-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

1-Benzyloxy-4-ethyl-2-methoxy-benzene

A mixture of 4-ethyl-2-methoxy-phenol [5.5 g (0.036 mol)], Benzylbromide [12.3 g (0.072 mol)], K₂CO₃ [10 g (0.072 mol) in 73 mL of ACNwas refluxed overnight. The reaction mixture was then rotary evaporatedand the residue treated with water then extracted with EtOAc. Theextract was washed with sat. NaCl, dried (MgSO₄) and the solventremoved.

Yield=8.7 g (quant) MS (m/z): 243 [M+H]

(E)-3-(5-Benzyloxy-2-ethyl-4-methoxy-phenyl)prop-2-enoic acid

The compound 1-benzyloxy-4-ethyl-2-methoxy-benzene [8.7 g (0.036 mol)]was added to a mixture of POCl₃ [20 mL (0.21 mol)] and DMF [17 g (0.22mol)] with stirring at 0° C. The viscous mixture was then heated to 80°C. and stirred there for 4 h. The reaction mix was then poured onto iceand then extracted with Et₂O. The extract was dried (MgSO₄) and thesolvent removed. Flash chrom. with 10% EtOAc/Hexane afforded the desiredaldehyde [3 g (0.011 mol)] 31% yield.

A mixture of the above aldehyde [3 g (0.011 mol)], malonic acid [2.2 g(0.022 mol)], pyridine (7 mL) and piperidine (0.2 mL) was stirred at 80°C. for 1 h followed by stirring for 3 h at 115° C. The reaction was thenpoured into water (200 mL) and acidified with conc. HCl. The resultingwhite ppt. was filtered and vacuum dried. Yield=3.2 g (29% overall) MS(m/z): 313 [M+H]

(E)-3-(5-Benzyloxy-2-ethyl-4-methoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]prop-2-enamide

To a mixture of (E)-3-(4,5-dimethoxy-2-ethyl-phenyl)prop-2-enoic acid[393 mg (1.7 mmol)], 2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [257 mg(1 mmol)], DMF (10 mL) and DIEA (1 mL (6 mmol) was added HATU [950 mg(2.5 mmol)]. The reaction mix was stirred at room temperature 2 h thendiluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. The EtOAclayer was dried (MgSO₄) and the solvent removed. Yield=310 mg (54% afterflash with 10% MeOH/DCM) MS (m/z): 552 [M+H]

6-Benzyloxy-1-[(E)-2-(5-benzyloxy-2-ethyl-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

To a solution of(E)-3-(5-benzyloxy-2-ethyl-4-methoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]prop-2-enamide[310 mg (0.563 mmol)] in ACN (13 mL) was added, under reflux, POCl₃ [361ul (3.9 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 mL ofchloroform and was then treated with 20 mL of 2N KOH and 50 mL of Et₂O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na₂SO₄) and thesolvent removed. The dark oil was the dissolved into 8 mL of dry EtOHand then treated with NaBH₄ [15 mg (0.395 mmol)]. The mixture wasstirred for 1 h at room temperature and the resulting solid wascarefully filtered off and dried. The solid was triturated with 50/50ACN/water, filtered and vacuum dried. Yield=150 mg (50% overall) MS(m/z): 536 [M+H]

Example AB6-benzyloxy-1-[(E)-2-(3-benzyloxy-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

2-(3-(Benzyloxy)-4-methoxyphenyl)ethanamine

were prepared as described in detail above.

(E)-3-(3-(Benzyloxy)-4-methoxyphenyl)acrylic acid

were prepared as described in detail above.

(E)-N-(3-(Benzyloxy)-4-methoxyphenethyl)-3-(3-(benzyloxy)-4-methoxyphenyl)acrylamide

To the mixture of (E)-3-(3-(benzyloxy)-4-methoxyphenyl)acrylic acid (3.3g, 11.61 mmol), 2-(3-(benzyloxy)-4-methoxyphenyl)ethanamine (4.45 g,17.30 mmol) and HATU (6.58 g, 17.31 mmol) in DMF (100 mL) was addedDIPEA (10 mL, 57.41 mmol). The resulting solution was stirred at roomtemperature for 2 hrs, diluted with EtOAc (300 mL), washed with brine,dried (Na₂SO₄), filtered, concentrated and purified by flashchromatography using MeOH (NH₃)/CHCl₃ gradient to afford 10 in 50%yield. M+H=524.

(E)-6-(Benzyloxy)-1-(3-(benzyloxy)-4-methoxystyryl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

The mixture of(E)-N-(3-(benzyloxy)-4-methoxyphenethyl)-3-(3-(benzyloxy)-4-methoxyphenyl)acrylamide(2.5 g, 4.77 mmol) and acetonitrile (90 mL) was stirred and heated toreflux, POCl3 (3.3 mL, 35.40 mmol) was added dropwise. The resultingreddish mixture was stirred and heated to reflux for 1 hr and treated asdescribed in detail for(E)-7-(benzyloxy)-1-(4-(benzyloxy)-3-methoxystyryl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline.The crude obtained was purified on the Shimadzu HPLC system to affordthe titled compound as the TFA salt. M+H (Neutral)=508.

Example AC6-benzyloxy-1-[(E)-2-(5-benzyloxy-2-chloro-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

5-Benzyloxy-2-chloro-4-methoxy-benzaldehyde

A mixture of 3-benzyloxy-4-methoxy-benzaldehyde [5 g (0.021 mol)] andNCS [3.4 g (0.0252 mol)] in 50 mL of DMF was heated to 70° C. andstirred there for 3 h. After cooling water was added and the resultingppt. was filtered off and dried under high vacuum. Yield=2 g (34%) afterflash chrom with DCM/Hexane MS (m/z): 277 [M+H]

(E)-3-(5-Benzyloxy-2-chloro-4-methoxy-phenyl)prop-2-enoic acid

A mixture of 5-benzyloxy-2-chloro-4-methoxy-benzaldehyde [2 g (0.072mol)], malonic acid [1.5 g (0.014 mol)], pyridine (4 mL) and piperidine(0.150 mL) was stirred at 80° C. for 1 h followed by stirring for 3 h at115° C. The reaction was then poured into water (200 mL) and acidifiedwith conc. HCl. The resulting white ppt., product, was filtered andvacuum dried. Yield=2.2 g (96%) MS (m/z): 319 [M+H]

(E)-3-(5-Benzyloxy-2-chloro-4-methoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]prop-2-enamide

To a mixture of(E)-3-(5-benzyloxy-2-chloro-4-methoxy-phenyl)prop-2-enoic acid [318 mg(1 mmol)], 2-(3-benzyloxy-4-methoxy-phenyl)ethanamine 150 mg (0.6mmol)], DMF (5 mL) and DIEA [0.5 mL (3 mmol)] was added HATU [475 mg(1.25 mmol)]. The reaction mix was stirred at room temperature 2 h thendiluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. The EtOAclayer was dried (MgSO₄) and the solvent removed. Yield=256 mg (74% afterflash with 10% MeOH/DCM) MS (m/z): 558 [M+H]

6-Benzyloxy-1-[(E)-2-(5-benzyloxy-2-chloro-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

To a solution of(E)-3-(5-benzyloxy-2-chloro-4-methoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]prop-2-enamide[256 mg (0.46 mmol)] in ACN (9 mL) was added, under reflux, POCl₃ [300ul (3.21 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 mL ofchloroform and was then treated with 20 mL of 2N KOH and 50 mL of Et₂O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na₂SO₄) and thesolvent removed. The dark oil was the dissolved in 8 mL of dry EtOH andthen treated with NaBH₄ [12 mg (0.32 mmol)]. The mixture was stirred for1 h at room temperature and the resulting solid was carefully filteredoff and dried. The solid was triturated with 50/50 ACN/water, filteredand vacuum dried. Yield=126 mg (51% overall) MS (m/z): 542 [M+H]

Example AD6-benzyloxy-1-[(E)-2-(5-benzyloxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

5-(Benzyloxy)-2-methylbenzaldehyde

5-Hydroxy-2-methylbenzaldehyde (2.07 g, 15.20 mmol) was combined withbenzylbromide (2.71 mL, 22.8 mmol) and Cs₂CO₃ (9.91 g, 30.4 mmol) in DMF(100 mL). The resulting mixture was stirred at 80° C. overnight. Uponconsumption of the starting material by TLC analysis, the reaction wasallowed to cool to room temperature. The organic solvent was removedunder reduced pressure. The residue obtained was purified by flashchromatography to afford the titled compound LCMS: M+1=227.3.

(E)-3-(5-(Benzyloxy)-2-methylphenyl)acrylic acid

5-(Benzyloxy)-2-methylbenzaldehyde (3.00 g, 13.26 mmol) was dissolved inpyridine (50 mL) along with malonic acid (2.78 g, 26.52 mmol) and acatalytic amount of piperidine (0.35 mL). The resulting mixture washeated at reflux for 18 hours, then the reaction mixture was allowed tocool to room temperature. The reaction was poured into ice cold 1M H₃PO₄(100 mL) and the resulting mixture was stirred for 10 minutes, the solidprecipitate was filtered, washed with water and dried over P₂O₅overnight. LCMS: M+1=269.3.

(E)-4-(Benzyloxy)-2-(2-bromovinyl)-1-methylbenzene

The solution of (E)-3-(5-(benzyloxy)-2-methylphenyl)acrylic acid (1.00g, 3.73 mmol) in CH₂Cl₂ (20 mL) with Et₃N (0.025 mL, 0.184 mmol) wasstirred for 5 minutes. To this solution was added NBS (809 mg, 4.42mmol) portionwise, as the reaction gave off CO₂ gas. After all theadditions the reaction mixture was stirred overnight. Additional NBS(809 mg, 4.42 mmol) was added and the mixture stirred for another 18hours. Upon complete reaction by TLC indication, it was purified byflash silica gel chromatography to furnish the titled compound.

(E)-6-(Benzyloxy)-1-(5-(benzyloxy)-2-methylstyryl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

A solution of (E)-4-(benzyloxy)-2-(2-bromovinyl)-1-methylbenzene (303mg, 1 mmol) was dissolved in dry Et₂O (15 mL) and cooled to −78° C. Asolution of t-BuLi (1.3 mL, 2.2 mmol, 1.7M in pentane) was addeddropwise and the resulting solution was stirred at −78° C. for 1 hourbefore a solution of 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline(134 mg, 0.5 mmol) in THF (3 mL) was added dropwise. The resultingmixture was stirred for 2 hours at −78° C. and then quenched with sat.aqueous NH₄Cl solution. The mixture was extracted with EtOAc and thecombined organic layers were dried over MgSO₄, filtered and evaporatedto dryness. The residue obtained was purified by flash silica gelchromatography to afford the titled compound. LCMS: M+1=492.6.

Examples AE/AF6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydroisoquinolineand6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

O-Benzylisovanillin

A mixture of isovanillin (10.0 g, 66 mmol), benzyl chloride (16.7 g,15.2 mL, 131 mmol), and anhydrous K₂CO₃ (6.4 g, 46 mmol) in EtOH (100mL) was refluxed for 5 h. After being stirred, the reaction mixture wasconcentrated to dryness and redissolved in 100 mL of CH₂Cl₂, and then 5%aqueous NaOH (3×50 mL) was added. The organic layer was washed withbrine (2×50 mL) and H₂O (2×50 mL), dried with anhydrous Na₂SO₄, andevaporated to dryness. Needles were obtained after crystallization fromMeOH/CH₂Cl₂ corresponding toO-benzylisovanillin(3-benzyloxy-4-methoxybenzaldehyde, 15 g, 94%).

3-Benzyloxy-4-methoxy-β-nitrostyrene

A mixture of O-benzylisovanillin (15.0 g, 61.9 mmol), nitromethane(11.34 g, 10.0 mL, 186 mmol), and NH₄OAc (11.9 g, 155 mmol) in AcOH (100mL) was refluxed for 4 h. After cooling, the mixture was diluted withH₂O (100 mL) and extracted with CH₂Cl₂ (3×30 mL). The organic solutionwas washed with brine (2×50 mL) and H₂O (2×30 mL), dried with anhydrousNa₂SO₄ and evaporated to dryness. Yellow needles were obtained afterrecrystallization from EtOH affording the3-benzyloxy-4-methoxy-â-nitrostyrene (15.4 g, 87%).

β-(3-Benzyloxy-4-methoxyphenyl)ethylamine

A solution of 3-benzyloxy-4-methoxy-O-nitrostyrene (11.1 g, 39 mmol) in150 mL of anhydrous THF was added dropwise to a vigorously stirredsuspension of LiAlH₄ (5.9 g, 156 mmol) in 120 mL of anhydrous Et₂O undernitrogen atmosphere and was refluxed for 16 h. After the solution wascooled, the excess reagent was destroyed by dropwise addition of H₂O and15% aqueous NaOH. After partial evaporation of the filtered portion, theaqueous solution was extracted with CH₂Cl₂ (3×50 mL) and the organiclayers were treated with 5% aqueous HCl. The resulting aqueous acidlayer was made basic (5% aqueous NH₄OH, pH 9) and extracted with CH₂Cl₂.The organic solution was washed with brine (2×50 mL) and H₂O (2×50 mL),dried with anhydrous K₂CO₃, and evaporated to dryness, to affordβ-(3-benzyloxy-4-methoxyphenyl) ethylamine (6.8 g, 69%) as an oil.

1-(Benzyloxy)-2-methoxy-4-methylbenzene

To a solution of 2-methoxy-4-methylphenol (10.0 g, 72.4 mmol) in 145 mLof CH₃CN was added K₂CO₃ (20.0 g, 145 mmol) and benzyl bromide (24.8 g,145 mmol). The resulting mixture was refluxed for 18 h and the solventwas removed with a rotary evaporator. The residue was treated with H₂Oand extracted with EtOAc (3×50 mL). The combined organic extracts werewashed with brine, dried over MgSO4, and concentrated in vacuo. Theresidue was purified by silica gel flash column chromatography (10%EtOAc/hexanes) to yield 1-(benzyloxy)-2-methoxy-4-methylbenzene (16.2 g,98%).

5-Benzyloxy-4-methoxy-2-methylbenzaldehyde

To a mixture of POCl₃ (60.9 g, 397 mmol) and DMF (29.0 g, 397 mmol) at0° C. was added 1-(benzyloxy)-2-methoxy-4-methylbenzene (15.1 g, 66mmol). The resulting solution was heated to 80° C. and stirred for 4 h.After being cooled to room temperature, the reaction mixture was pouredinto ice and extracted with ether. The combined extracts wereconcentrated in vacuo and purified by silica gel flash columnchromatography (10% EtOAc/hexanes) to afford benzaldehyde 10 (12.0 g,71%) as a white solid.

2-Methyl-4-methoxy-5-benzyloxycinnamic acid

5-Benzyloxy-4-methoxy-2-methylbenzaldehyde (13.5 g, 52.7 mM), malonicacid (11.0 g, 105.4 mM), pyridine (30 mL), and piperidine (0.9 g, 1.0mL, 11 mmol) were mixed well, heated to 80-85° C. for 1 h and finallyrefluxed (110-115° C.) for an additional 3 h. The reaction mixture waspoured into water and acidified with concentrated HCl. The precipitateobtained was filtered, and washed with cold water repeatedly. Theresidue was dissolved in NaOH, diluted, again acidified, the precipitatewas collected washed with cold water and dried under high vacuum overP₂O₅ and used without further purifications.

(E)-3-(5-(Benzyloxy)-4-methoxy-2-methylphenyl)-N-(3-(benzyloxy)-4-methoxyphenethyl)acrylamide

To the stirred solution of the 2-methyl-4-methoxy-5-benzyloxycinnamicacid (3.0 g, 10.0 mmol) and β-(3-benzyloxy-4-methoxyphenyl)ethylamine(2.6 g, 10.0 mmol) in DMF (40 mL) was added HATU (5.7 g, 15 mmol)followed by diisopropylethylamine (1.95 g, 2.6 mL, 15.0 mmol). Thereaction mixture was stirred at room temperature for 1 h. The solutionwas diluted with EtOAc (50 mL), washed with 10% citric acid, saturatedaqueous solution of NaHCO₃, dried (Na₂SO₄), filtered and was purified byflash chromatography Yield 3.5 g (65%).

(E)-6-(benzyloxy)-1-(5-(benzyloxy)-4-methoxy-2-methylstyryl)-7-methoxy-3,4-dihydroisoquinolineand(E)-6-(Benzyloxy)-1-(5-(benzyloxy)-4-methoxy-2-methylstyryl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

The amide (200 mg, 0.37 mmol) was suspended in dry acetonitrile (10 mL).The stirred mixture was heated to reflux. Then phosphorus oxychloride(400 mg, 0.24 mL, 2.6 mmol) was added drop wise. The reflux wascontinued for a further 1 h. The solution was evaporated thoroughly todryness under high vacuum to remove the excess of POCI₃. The residue wasdissolved in chloroform (10 mL), shaken with 2M KOH (10 mL) and ether(20 mL). The separated upper layer was washed with water (2×10 mL) andevaporated in vacuo to give an oil. A portion of the material waspurified and isolated as Example AE. The remaining material wasdissolved in ethanol (8 mL) sodium borohydride (9.8 mg, 0.26 mmol) wasadded. The mixture was stirred at room temperature for 30 min. Theexcess reagent was destroyed by dropwise addition of 2M HCl. Thereaction mixture was basified with 2M NaOH. Most of the ethanol wasremoved in vacuo. The residue was partitioned between water (10 mL) andchloroform (10 mL). The organic layer was washed with water (2×10 mL).The solvent was removed in vacuo. The residue was purified by columnchromatography to afford the titled isoquinoline (0.12 g, 62%).

Example AG6-benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-2-methyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

(E)-3-(4-Methoxy-2-methylphenyl)acrylic acid

4-Methoxy-2-methylbenzaldehyde (5.0 g, 33.3 mmol) was dissolved inpyridine (14 mL) along with malonic acid (6.93 g, 66.58 mmol) and acatalytic amount of piperidine (0.5 mL). The resulting mixture washeated at reflux for 18 hours. After the starting material was consumed,the reaction mixture was allowed to cool to room temperature. Thereaction was poured into ice cold 1M H₃PO₄ (100 mL) and the resultingmixture was stirred for 10 minutes and the solid was filtered off. Thesolid was washed with water and dried over P₂O₅ overnight. LCMS:M+1=193.2

(E)-1-(2-Bromovinyl)-4-methoxy-2-methylbenzene

The (E)-3-(4-methoxy-2-methylphenyl)acrylic acid (1.93 g, 10.06 mmol)was stirred in CH₂Cl₂ (30 mL) along with Et₃N (0.069 mL, 0.502 mmol) for5 minutes. To this solution was added NBS (2.14 g, 12.04 mmol) inportions, as the reaction gave off CO₂ gas. The reaction mixture wasallowed to stir overnight. After TLC analysis indicated completereaction it was purified by flash silica gel chromatography to afford(1.95 g) of a solid.

(E)-6-(Benzyloxy)-7-methoxy-1-(4-methoxy-2-methylstyryl)-1,2,3,4-tetrahydroisoquinoline

A solution of (E)-1-(2-bromovinyl)-4-methoxy-2-methylbenzene (228 mg, 1mmol) was dissolved in dry Et₂O (15 mL) and cooled to −78° C. A solutionof t-BuLi (1.3 mL, 2.2 mmol, 1.7M in pentane) was added dropwise and theresulting solution was stirred at −78° C. for 1 hour before a solutionof 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline (134 mg, 0.5 mmol) inTHF (3 mL) was added dropwise. The resulting mixture was stirred for 2hours at −78° C. and then quenched with sat. aqueous NH₄Cl solution. Themixture was extracted with EtOAc and the combined organic layers weredried over MgSO₄, filtered and evaporated to dryness. The residueobtained was purified by flash silica gel chromatography to afford thetitled compound. LCMS: M+1=416.6.

Example AH6-benzyloxy-1-[(E)-2-(4,5-dimethoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-3-(4,5-Dimethoxy-2-methyl-phenyl)prop-2-enoic acid

The compound 1,2-dimethoxy-4-methyl-benzene [25 g (0.164 mol)] was addedto a mixture of POCl₃ [151 g (0.987 mol)] and DMF [73 g (1 mol)] withstirring at 0° C. The viscous mixture was then heated to 80° C. andstirred there for 4 h. The reaction mix was then poured onto ice andthen extracted with Et₂O. The extract was dried (MgSO₄) and the solventremoved. Flash chrom. with 10% EtOAc/Hexane afforded the desiredaldehyde [26 g (0.144 mol)] 88% yield.

A mixture of the above aldehyde [5.4 g (0.03 mol)], malonic acid [6.24 g(0.06 mol)], pyridine (20 mL) and piperidine (0.5 mL) was stirred at 80°C. for 1 h followed by stirring for 3 h at 115° C. The reaction was thenpoured into water (200 mL) and acidified with conc. HCl. The resultingwhite ppt. was filtered and vacuum dried. Yield=4.8 g (63% overall) MS(m/z): 223 [M+H]

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(4,5-dimethoxy-2-methyl-phenyl)prop-2-enamide

To a mixture of (E)-3-(4,5-dimethoxy-2-methyl-phenyl)prop-2-enoic acid[444 mg (2 mmol)], 2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [300 mg(1.2 mmol)], DMF (10 mL) and DIEA (1 mL (6 mmol) was added HATU [950 mg(2.5 mmol)]. The reaction mix was stirred at room temperature 2 h thendiluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. The EtOAclayer was dried (MgSO₄) and the solvent removed. Yield=300 mg (54% afterflash with 10% MeOH/DCM) MS (m/z): 462 [M+H]

6-Benzyloxy-1-[(E)-2-(4,5-dimethoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(4,5-dimethoxy-2-methyl-phenyl)prop-2-enamide[300 mg (0.651 mmol)] in ACN (13 mL) was added, under reflux, POCl₃ [417ul (4.5 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 mL ofchloroform and was then treated with 20 mL of 2N KOH and 50 mL of Et₂O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na₂SO₄) and thesolvent removed. The dark oil was the dissolved into 8 mL of dry EtOHand then treated with NaBH₄ [17 mg (0.447 mmol)]. The mixture wasstirred for 1 h at room temperature and the resulting solid wascarefully filtered off and dried. The solid was triturated with 50/50ACN/water, filtered and vacuum dried. Yield=124 mg (44% overall) MS(m/z): 446 [M+H]

Example AI(E)-6-(benzyloxy)-7-methoxy-1-(4-methoxy-2-(4-methoxybutoxy)styryl)-1,2,3,4-tetrahydroisoquinoline

To the solution of 2-hydroxy-methoxybenzaldehyde1 (1.0 g, 6.57 mmol) inanhydrous acetonitrile (20 ml) under argon was added Cs₂CO₃ (2.14 g,6.58 mmol), the resulting mixture was stirred at room temperature for 30mins, then 1-bromo-4-methoxybutane 2 (1.1 g, 6.58 mmol) was added. Theresulting mixture was stirred at room temperature overnight. Thevolatiles were removed, partitioned between water and EtOAc. The organiclayer was washed with brine, dried (Na₂SO₄), filtered, concentrated todryness and purified on the ISCO using EtOAc/Hexanes gradient to afford4-methoxy-2-(4-methoxybutoxy)benzaldehyde 3. The(E)-3-(4-methoxy-2-(4-methoxybutoxy)phenyl)acrylic acid 5 was preparedby the Knoevenagel condensation reaction as described in detail in thefirst patent writeup.

To the mixture of 5 (0.9542 g, 3.40 mmol),2-(3-(benzyloxy)-4-methoxyphenyl)ethanamine hydrochloride 6 (1.2 g,4.085 mmol), HATU (1.55 g, 4.085 mmol) in anhydrous DMF (25 ml) wasadded DIEA (5 ml, 28.70 mmol). The resulting mixture was stirred at roomtemperature for 2 hrs, diluted with EtOAc and washed with brine. Theorganic layer was dried (Na₂SO₄), filtered, concentrated and purified onthe ISCO using EtOAc/Hexanes gradient to furnish the acrylamide 7. Tothe mixture of the acrylamide in anhydrous acetonitrile (60 ml) wasadded POCl₃ (5 ml, 53.64 mmol), stirred and heated to reflux monitoredby LCMS. Ca 1 hr, the reaction was worked up as described in detail onthe first patent writeup. NaBH₄ reduction of the imine in EtOH affordedthe titled compound. M+H=504.

Example AJ(E)-6-(benzyloxy)-7-methoxy-1-(2-methyl-4-(trifluoromethoxy)styryl)-1,2,3,4-tetrahydroisoquinoline

To the mixture of the acrylamide 9 (1.0 g, 2.06 mmol) obtained by theHATU coupling of 8 and 9 described in detail in Example AI, in anhydrousacetonitrile (25 ml), was stirred and heated to reflux, to the solutionwas added POCl₃ (2 ml). The reaction was carried out as described indetails in the provisional writeup. The imine obtained was subjected tothe NaBH₄ reduction in EtOH. After the usual workup, the crude obtainedwas purified by HPLC to afford the titled compound as the TFA salt.M+H=470, M+H+TFA=584.

Example AK6-benzyloxy-7-methoxy-1-[(E)-2-(2-methylpyrazol-3-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

(E)-3-(2-Methylpyrazol-3-yl)prop-2-enoic acid: A mixture of2-methylpyrazole-3-carbaldehyde [0.286 g (0.0026 mol)], malonic acid[0.53 g (0.0052 mol)], pyridine (5 mL) and piperidine (0.050 mL) wasstirred at 80° C. for 1 h followed by stirring for 3 h at 115° C. Thereaction was then poured into water (100 mL) and acidified with conc.HCl. The resulting white ppt., product, was filtered and vacuum dried.Yield=395 mg (99%) MS (m/z): 153 [M+H]

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(2-methylpyrazol-3-yl)prop-2-enamide:To a mixture of (E)-3-(2-Methylpyrazol-3-yl)prop-2-enoic acid [304 mg (2mmol)], 2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [514 mg (2 mmol)],DMF (8 mL) and DIEA [1 mL (6 mmol)] was added HATU [950 mg (2.5 mmol)].The reaction mix was stirred at room temperature 2 h then diluted with50 mL of EtOAc and washed 2× with sat. NaCl aq. The EtOAc layer wasdried (MgSO₄) and the solvent removed. Yield=800 mg (99% after flashwith 10% MeOH/DCM) MS (m/z): 392 [M+H]

6-Benzyloxy-7-methoxy-1-[(E)-2-(2-methylpyrazol-3-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(2-methylpyrazol-3-yl)prop-2-enamide[800 mg (2 mmol)] in ACN (30 ml) was added, under reflux, POCl₃ [1000 ul(11 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 ml ofchloroform and was then treated with 20 ml of 2N KOH and 50 ml of Et₂O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na2SO4) and thesolvent removed. The dark oil was the dissolved into 24 ml of dry MeOHand then treated with NaBH₄ [60 mg (1.65 mmol)]. The mixture was stirredfor 1 h at room temperature. A light yellow solid ppt′d out of solution,was filtered off, triturated with 0.1% TFA and then dried in vacuo.Yield=500 mg (64%) as TFA salt. MS (m/z): 376 [M+H]

Example AL6-Benzyloxy-1-[(E)-2-(1-ethylpyrazol-4-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-3-(1-Ethylpyrazol-4-yl)prop-2-enoic acid: A mixture of1-ethylpyrazole-4-carbaldehyde [0.322 g (2.6 mmol)], malonic acid [0.530g (5.2 mmol)], pyridine (5 mL) and piperidine (0.050 mL) was stirred at80° C. for 1 h followed by stirring for 3 h at 115° C. The reaction wasthen poured into water (100 mL) and acidified with conc. HCl. Theresulting white ppt., product, was filtered and vacuum dried. Yield=436mg (99%) MS (m/z): 169 [M+H]

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(1-ethylpyrazol-4-yl)prop-2-enamide:To a mixture of (E)-3-(1-Ethylpyrazol-4-yl)prop-2-enoic acid [370 mg(2.2 mmol)], 2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [565 mg (2.2mmol)], DMF (8 mL) and DIEA [1 mL (6 mmol)] was added HATU [950 mg (2.5mmol)]. The reaction mix was stirred at room temperature 2 h thendiluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. The EtOAclayer was dried (MgSO4) and the solvent removed. Yield=900 mg (99%)after flash with 10% MeOH/DCM) MS (m/z): 406 [M+H]

6-Benzyloxy-1-[(E)-2-(1-ethylpyrazol-4-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(1-ethylpyrazol-4-yl)prop-2-enamide[900 mg (2.2 mmol)] in ACN (30 ml) was added, under reflux, POCl₃ [1000ul (11 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 ml ofchloroform and was then treated with 20 ml of 2N KOH and 50 ml of Et₂O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na₂SO₄) and thesolvent removed. The dark oil was the dissolved into 24 ml of dry MeOHand then treated with NaBH₄ [60 mg (1.65 mmol)]. The mixture was stirredfor 1 h at room temperature. A light yellow solid ppt′d out of solution,was filtered off, triturated with 0.1% TFA and then dried in vacuo.Yield=600 mg (70%) as TFA salt. MS (m/z): 390 [M+H]

Example AM6-Benzyloxy-7-methoxy-1-[(E)-2-(3,4,5-trimethoxyphenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

(E)-3-(3,4,5-Trimethoxyphenyl)prop-2-enoic acid: A mixture of3,4,5-trimethoxybenzaldehyde [0.5 g (0.0026 mol)], malonic acid [0.53 g(0.0052 mol)], pyridine (5 mL) and piperidine (0.050 mL) was stirred at80° C. for 1 h followed by stirring for 3 h at 115° C. The reaction wasthen poured into water (100 mL) and acidified with conc. HCl. Theresulting white ppt., product, was filtered and vacuum dried. Yield=530mg (86%) MS (m/z): 239 [M+H]

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(3,4,5-trimethoxyphenyl)prop-2-enamide:To a suspension of (E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoic acid[0.530 g (0.0022 mol)] in 20 ml of Dichloromethane was added 2 drops ofDMF followed by oxalyl chloride [271 ul (3.2 mol)]. After 1 h stirringat room temperature the reaction was rotary evaporated to dryness andthe resulting yellow residue was dried in vacuo. To a solution of2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [565 mg (2.2 mmol)] and DIEA[1 mL (6 mmol)] in 20 ml of Dichloromethane was added dropwise, at icebath temperature, the crude yellow acyl chloride dissolved in 4 ml ofDichloromethane. The reaction mix was then stirred at room temperature 2h then diluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. TheEtOAc layer was dried (MgSO4) and the solvent removed. Yield=1 g (99%)after flash with 10% MeOH/DCM) MS (m/z): 478 [M+H]

6-Benzyloxy-7-methoxy-1-[(E)-2-(3,4,5-trimethoxyphenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(3,4,5-trimethoxyphenyl)prop-2-enamide[1000 mg (2.2 mmol)] in ACN (45 ml) was added, under reflux, POCl₃ [1500ul (16 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 ml ofchloroform and was then treated with 20 ml of 2N KOH and 50 ml of Et₂O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na2SO4) and thesolvent removed. The dark oil was the dissolved into 24 ml of dry MeOHand then treated with NaBH₄ [60 mg (1.65 mmol)] at 00. The mixture wasstirred for 1 h at room temperature. An off white solid ppt′d out ofsolution, was filtered off, triturated with 0.1% TFA and then dried invacuo. Yield=605 mg (60%) as TFA salt. MS (m/z): 462 [M+H]

Example AN6-Benzyloxy-7-methoxy-1-[(E)-2-(7-methoxybenzofuran-4-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

7-methoxybenzofuran-4-carbaldehyde: To a mixture of POCl3 (0.65 ml, 0.04mol) and DMF (2.1 ml, 0.04 mol) at 0° C. was added 7-methoxybenzofuran(1 g, 0.0067 mol). The resulting solution was heated to 80° C. andstirred for 4 h. After being cooled to room temperature, the reactionmixture was poured into ice and extracted with ether. The combinedextracts were concentrated in vacuo and purified by silica gel flashcolumn chromatography (10% EtOAc/hexanes) to afford benzaldehyde (750mg, 64%) as an off-white solid.

(E)-3-(7-Methoxybenzofuran-4-yl)prop-2-enoic acid:7-methoxybenzofuran-4-carbaldehyde (0.4 g, 0.0023 mol), malonic acid(0.53 g, 0.0052 mol), pyridine (5 mL), and piperidine (50 ul, 0.5 mmol)were mixed well, heated to 80-85° C. for 1 h and finally refluxed(110-115° C.) for an additional 3 h. The reaction mixture was pouredinto water and acidified with concentrated HCl. The precipitate obtainedwas filtered, and washed with cold water repeatedly. The residue wasdissolved in NaOH, diluted, again acidified, the precipitate wascollected washed with cold water and dried under high vacuum over P₂O₅and used without further purifications. Yield=444 mg.

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(7-methoxybenzofuran-4-yl)prop-2-enamide:To a suspension of (E)-3-(7-methoxybenzofuran-4-yl)prop-2-enoic acid[444 mg (0.002 mol)] in 20 ml of Dichloromethane was added 2 drops ofDMF followed by oxalyl chloride [271 ul (3.2 mol)]. After 1 h stirringat room temperature the reaction was rotary evaporated to dryness andthe resulting yellow residue was dried in vacuo. To a solution of2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [565 mg (2.2 mmol)] and DIEA[1 mL (6 mmol)] in 20 ml of Dichloromethane was added dropwise, at icebath temperature, the crude yellow acyl chloride dissolved in 4 ml ofDichloromethane. The reaction mix was then stirred at room temperature 2h then diluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. TheEtOAc layer was dried (MgSO4) and the solvent removed. Yield=0.850 g(93%) after flash chromatography with 10% MeOH/DCM).

6-Benzyloxy-7-methoxy-1-[(E)-2-(7-methoxybenzofuran-4-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(7-methoxybenzofuran-4-yl)prop-2-enamide[850 mg (1.85 mmol)] in ACN (30 ml) was added, under reflux, POCl₃ [1000ul (11 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 ml ofchloroform and was then treated with 20 ml of 2N KOH and 50 ml of Et₂O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na₂SO₄) and thesolvent removed. The dark oil was the dissolved into 24 ml of dry MeOHand then treated with NaBH₄ [60 mg (1.65 mmol)]. The mixture was stirredfor 1 h at room temperature. A light yellow solid ppt′d out of solution,was filtered off, triturated with 0.1% TFA and then dried in vacuo.Yield=700 mg (84%) as TFA salt. MS (m/z): 442 [M+H]

Example AO6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxybenzofuran-7-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

4-Methoxybenzofuran-7-carbaldehyde: To a solution of7-bromo-4-methoxy-benzofuran (1.1 g (5 mmol) in THF (13 ml) at −78° C.was added 1.6M n-BuLi (3.4 ml, 5.5 mmol). The resulting solution wasstirred at −75° C. for 40 min followed by the addition of DMF (0.401 ml,5.5 mmol). The mixture was allowed to warm slowly to room temperatureand stirred overnight. The reaction was quenched with NH₄Cl sat andextracted with Et₂O. The extracts were dried (Na₂SO₄) and the solventremoved. Yield=528 mg after trituration with hexane.

(E)-3-(4-methoxybenzofuran-7-yl)prop-2-enoic acid:4-methoxybenzofuran-7-carbaldehyde (0.4 g, 0.0023 mol), malonic acid(0.53 g, 0.0052 mol), pyridine (5 mL), and piperidine (50 ul, 0.5 mmol)were mixed well, heated to 80-85° C. for 1 h and finally refluxed(110-115° C.) for an additional 3 h. The reaction mixture was pouredinto water and acidified with concentrated HCl. The precipitate obtainedwas filtered, and washed with cold water repeatedly. The residue wasdissolved in NaOH, diluted, again acidified, the precipitate wascollected washed with cold water and dried under high vacuum over P₂O₅and used without further purifications. Yield=444 mg.

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(7-methoxybenzofuran-4-yl)prop-2-enamide:To a suspension of (E)-3-(4-methoxybenzofuran-7-yl)prop-2-enoic acid[444 mg (0.002 mol)] in 20 ml of Dichloromethane was added 2 drops ofDMF followed by oxalyl chloride [271 ul (3.2 mol)]. After 1 h stirringat room temperature the reaction was rotary evaporated to dryness andthe resulting yellow residue was dried in vacuo. To a solution of2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [565 mg (2.2 mmol)] and DIEA[1 mL (6 mmol)] in 20 ml of Dichloromethane was added dropwise, at icebath temperature, the crude yellow acyl chloride dissolved in 4 ml ofDichloromethane. The reaction mix was then stirred at room temperature 2h then diluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. TheEtOAc layer was dried (MgSO₄) and the solvent removed. Yield=0.847 g(93%) after flash chromatography with 10% MeOH/DCM)

6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxybenzofuran-7-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(4-methoxybenzofuran-7-yl)prop-2-enamide[315 mg (0.69 mmol)] in ACN (13 ml) was added, under reflux, POCl₃ [400ul (4.3 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 30 ml ofchloroform and was then treated with 30 ml of 2N KOH and 100 ml of Et2O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na₂SO₄) and thesolvent removed. The dark oil was the dissolved into 7 ml of dry MeOH(with 1 ml of DCM) and then treated with NaBH₄ [18 mg (0.47 mmol)]. Themixture was stirred for 1 h at room temperature. A light yellow solidppt′d out of solution, was filtered off, triturated with 0.1% TFA andthen dried in vacuo. Yield=300 mg (99%) as TFA salt. MS (m/z): 442 [M+H]

Example AP6-Benzyloxy-1-[(E)-2-(4-benzyloxy-3,5-dimethoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-3-(4-Benzyloxy-3,5-dimethoxy-phenyl)prop-2-enoic acid:4-benzyloxy-3,5-dimethoxy-benzaldehyde (0.71 g (0.0026 mmol)), malonicacid (0.53 g, 0.0052 mol), pyridine (5 mL), and piperidine (50 ul, 0.5mmol) were mixed well, heated to 80-85° C. for 1 h and finally refluxed(110-115° C.) for an additional 3 h. The reaction mixture was pouredinto water and acidified with concentrated HCl. The precipitate obtainedwas filtered, and washed with cold water repeatedly. The residue wasdissolved in NaOH, diluted, again acidified, the precipitate wascollected washed with cold water and dried under high vacuum over P₂O₅and used without further purifications. Yield=769 mg.

(E)-3-(4-Benzyloxy-3,5-dimethoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]prop-2-enamide:To a suspension of (E)-3-(4-benzyloxy-3,5-dimethoxy-phenyl)proEp-2-enoicacid [628 mg (0.002 mol)] in 20 ml of Dichloromethane was added 2 dropsof DMF followed by oxalyl chloride [271 ul (3.2 mol)]. After 1 hstirring at room temperature the reaction was rotary evaporated todryness and the resulting yellow residue was dried in vacuo. To asolution of 2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [565 mg (2.2mmol)] and DIEA [1 mL (6 mmol)] in 20 ml of Dichloromethane was addeddropwise, at ice bath temperature, the crude yellow acyl chloridedissolved in 4 ml of Dichloromethane. The reaction mix was then stirredat room temperature 2 h then diluted with 50 mL of EtOAc and washed 2×with sat. NaCl aq. The EtOAc layer was dried (MgSO₄) and the solventremoved. Yield=1.2 g (99%) after flash chromatography with 10% MeOH/DCM)

6-Benzyloxy-1-[(E)-2-(4-benzyloxy-3,5-dimethoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-3-(4-benzyloxy-3,5-dimethoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]prop-2-enamide [1200 mg (2.2 mmol)] in ACN (45 ml) was added, underreflux, POCl₃ [1500 ul (16 mmol)]. The reaction was stirred at refluxfor 10 min and then rotary evaporated to dryness. The residue was takenup into 10 ml of chloroform and was then treated with 20 ml of 2N KOHand 50 ml of Et2O. This mixture was rapidly stirred for 30 min at roomtemperature and the upper organic layer removed, washed with water,dried (Na₂SO₄) and the solvent removed. The dark oil was the dissolvedinto 24 ml of dry MeOH and then treated with NaBH₄ [60 mg (1.65 mmol)]at 00. The mixture was stirred for 1 h at room temperature. A off whitesolid ppt′d out of solution, was filtered off, triturated with 0.1% TFAand then dried in vacuo. Yield=571 mg (48% overall) as TFA salt. MS(m/z): 538 [M+H]

Example AQ6-Benzyloxy-7-methoxy-1-[(E)-2-(2,4,5-trimethoxyphenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

(E)-3-(2,4,5-Trimethoxyphenyl)prop-2-enoic acid:2,4,5-trimethoxybenzaldehyde (0.5 g, 0.0026 mol), malonic acid (0.53 g,0.0052 mol), pyridine (5 mL), and piperidine (50 ul, 0.5 mmol) weremixed well, heated to 80-85° C. for 1 h and finally refluxed (110-115°C.) for an additional 3 h. The reaction mixture was poured into waterand acidified with concentrated HCl. The precipitate obtained wasfiltered, and washed with cold water repeatedly. The residue wasdissolved in NaOH, diluted, again acidified, the precipitate wascollected washed with cold water and dried under high vacuum over P₂O₅and used without further purifications. Yield=594 mg.

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(2,4,5-trimethoxyphenyl)prop-2-enamide:To a solution of (E)-3-(2,4,5-trimethoxyphenyl)prop-2-enoic acid [594 mg(0.0025 mol)], 2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [565 mg (2.2mmol)] and DIEA [3 ml (0.0025 mol] in 9 ml of Dimethylforamide was addedHATU [1.3 g (0.0034 mol)]. After 1 h stirring at room temperature thereaction mix was then diluted with 50 mL of EtOAc and washed 2× withsat. NaCl aq. The EtOAc layer was dried (MgSO₄) and the solvent removed.Yield=1.2 (99%) after flash chromatography with 10% MeOH/DCM)

6-Benzyloxy-7-methoxy-1-[(E)-2-(2,4,5-trimethoxyphenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(2,4,5-trimethoxyphenyl)prop-2-enamide[1190 mg (2.5 mmol)] in ACN (45 ml) was added, under reflux, POCl₃ [1500ul (16 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 ml ofchloroform and was then treated with 20 ml of 2N KOH and 50 ml of Et2O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na2SO4) and thesolvent removed. The dark oil was the dissolved into 24 ml of dry MeOHand then treated with NaBH4 [60 mg (1.65 mmol)]. The mixture was stirredfor 1 h at room temperature. A light yellow solid ppt′d out of solution,was filtered off, triturated with 0.1% TFA and then dried in vacuo.Yield=295 mg (26% overall) as TFA salt. MS (m/z): 462 [M+H]

Example AR6-Benzyloxy-1-[(E)-2-(3-bromo-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-3-(3-Bromo-4-methoxy-phenyl)prop-2-enoic acid:3-bromo-4-methoxy-benzaldehyde (1 g (0.0046 mmol)), malonic acid (0.93g, 0.0092 mol), pyridine (9 mL), and piperidine (88 ul, 0.5 mmol) weremixed well, heated to 80-85° C. for 1 h and finally refluxed (110-115°C.) for an additional 3 h. The reaction mixture was poured into waterand acidified with concentrated HCl. The precipitate obtained wasfiltered, and washed with cold water repeatedly. The residue wasdissolved in NaOH, diluted, again acidified, the precipitate wascollected washed with cold water and dried under high vacuum over P₂O₅and used without further purifications. Yield=1.2 g.

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(3-bromo-4-methoxy-phenyl)prop-2-enamide:To a suspension of (E)-3-(3-bromo-4-methoxy-phenyl)prop-2-enoic acid[1.2 g (0.0046 mol)] in 20 ml of Dichloromethane was added 5 drops ofDMF followed by oxalyl chloride [613 ul (6.9 mol)]. After 1 h stirringat room temperature the reaction was rotary evaporated to dryness andthe resulting yellow residue was dried in vacuo. To a solution of2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [1.2 g (4.6 mmol)] and DIEA[1 mL (6 mmol)] in 20 ml of Dichloromethane was added dropwise, at icebath temperature, the crude yellow acyl chloride dissolved in 4 ml ofDichloromethane. The reaction mix was then stirred at room temperature 2h then diluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. TheEtOAc layer was dried (MgSO₄) and the solvent removed. Yield=2.3 g (99%)after flash chromatography with 10% MeOH/DCM)

6-Benzyloxy-1-[(E)-2-(3-bromo-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(3-bromo-4-methoxy-phenyl)prop-2-enamide[2.3 g (0.0046 mol)] in ACN (90 ml) was added, under reflux, POCl3 [3000ul (33 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 30 ml ofchloroform and was then treated with 30 ml of 2N KOH and 100 ml of Et2O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na2SO4) and thesolvent removed. The dark oil was the dissolved into 40 ml of dry MeOHand then treated with NaBH4 [120 mg (3.3 mmol)]. The mixture was stirredfor 1 h at room temperature. A light yellow solid ppt′d out of solution,was filtered off, triturated with 0.1% TFA and then dried in vacuo.Yield=2 g (91% overall) as TFA salt. MS (m/z): 480 [M+H]

Example AS6-Benzyloxy-1-[(E)-2-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-3-(5-Benzyloxy-2-tert-butyl-4-methoxy-phenyl)prop-2-enoic acid:5-benzyloxy-2-tert-butyl-4-methoxy-benzaldehyde (0.116 g (0.39 mmol)),malonic acid (83 g, 0.8 mol), pyridine (5 mL), and piperidine (88 ul,0.5 mmol) were mixed well, heated to 80-85° C. for 1 h and finallyrefluxed (110-115° C.) for an additional 3 h. The reaction mixture waspoured into water and acidified with concentrated HCl. The precipitateobtained was filtered, and washed with cold water repeatedly. Theresidue was dissolved in NaOH, diluted, again acidified, the precipitatewas collected washed with cold water and dried under high vacuum overP₂O₅ and used without further purifications. Yield=133 mg.

(E)-3-(5-Benzyloxy-2-tert-butyl-4-methoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]prop-2-enamide:To a suspension of(E)-3-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)prop-2-enoic acid [113mg (0.39 mmol)] in 10 ml of Dichloromethane was added 2 drops of DMFfollowed by oxalyl chloride [51 ul (0.6 mmol)]. After 1 h stirring atroom temperature the reaction was rotary evaporated to dryness and theresulting yellow residue was dried in vacuo. To a solution of2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [103 mg (0.4 mmol)] and DIEA[100 uL (0.6 mmol)] in 10 ml of Dichloromethane was added dropwise, atice bath temperature, the crude yellow acyl chloride dissolved in 4 mlof Dichloromethane. The reaction mix was then stirred at roomtemperature 2 h then diluted with 50 mL of EtOAc and washed 2× with sat.NaCl aq. The EtOAc layer was dried (MgSO₄) and the solvent removed.Yield=225 mg (99%) after flash chromatography with 10% MeOH/DCM)

6-Benzyloxy-1-[(E)-2-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-3-(5-benzyloxy-2-tert-butyl-4-methoxy-phenyl)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]prop-2-enamide[225 mg (0.39 mmol)] in ACN (9 ml) was added, under reflux, POCl₃ [300ul (3.21 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 ml ofchloroform and was then treated with 20 ml of 2N KOH and 50 ml of Et₂O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na₂SO₄) and thesolvent removed. The dark oil was the dissolved into 8 ml of dry EtOHand then treated with NaBH4 [12 mg (0.32 mmol)]. The mixture was stirredfor 1 h at room temperature and the resulting solid was carefullyfiltered off and dried. The solid was triturated with 50/50 ACN/water,filtered and vacuum dried. Yield=50 mg (11% overall) as TFA salt. MS(m/z): 564 [M+H]

Example AT6-Benzyloxy-1-[(E)-2-(3,5-dimethoxyphenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example AI at the same scale withthe aldehyde 3,5-dimethoxybenzaldehyde the reaction afforded the desiredadduct. Yield=30 mg (34%) as TFA salt via prep chrom. MS (m/z): 432[M+H]

Example AU6-benzyloxy-7-methoxy-1-[(E)-2-(2-methoxy-4-pyridyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

(E)-3-(6-Methoxy-3-pyridyl)prop-2-enoic acid:6-methoxypyridine-3-carbaldehyde (3 g (0.022 mol)), malonic acid (4.35 g(0.042 mol)), pyridine (15 mL), and piperidine (400 ul, 4 mmol) weremixed well, heated to 80-85° C. for 1 h and finally refluxed (110-115°C.) for an additional 3 h. The reaction mixture was poured into waterand acidified with concentrated HCl. The precipitate obtained wasfiltered, and washed with cold water repeatedly. The residue wasdissolved in NaOH, diluted, again acidified, the precipitate wascollected washed with cold water and dried under high vacuum over P₂O₅and used without further purifications. Yield=2.8 g.

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(2-methoxy-4-pyridyl)prop-2-enamide:To a suspension of (E)-3-(6-Methoxy-3-pyridyl)prop-2-enoic acid [179 mg(1 mmol)] in 10 ml of Dichloromethane was added 2 drops of DMF followedby oxalyl chloride [300 ul (3 mmol)]. After 1 h stirring at roomtemperature the reaction was rotary evaporated to dryness and theresulting yellow residue was dried in vacuo. To a solution of2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [257 mg (1 mmol)] and DIEA[500 uL (3 mmol)] in 10 ml of Dichloromethane was added dropwise, at icebath temperature, the crude yellow acyl chloride dissolved in 4 ml ofDichloromethane. The reaction mix was then stirred at room temperature 2h then diluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. TheEtOAc layer was dried (MgSO₄) and the solvent removed. Yield=286 mg(68%) after flash chromatography with 10% MeOH/DCM)

6-Benzyloxy-7-methoxy-1-[(E)-2-(2-methoxy-4-pyridyl)vinyl]-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(2-methoxy-4-pyridyl)prop-2-enamide[286 mg (0.68 mmol)] in ACN (9 ml) was added, under reflux, POCl₃ [600ul (6.42 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 ml ofchloroform and was then treated with 20 ml of 2N KOH and 50 ml of Et₂O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na₂SO₄) and thesolvent removed. The dark oil was the dissolved into 8 ml of dry EtOHand then treated with NaBH4 [12 mg (0.32 mmol)]. The mixture was stirredfor 1 h at room temperature and the resulting solid was carefullyfiltered off and dried. The solid was triturated with 50/50 ACN/water,filtered and vacuum dried. Yield=20 mg (8% overall) as TFA salt. MS(m/z): 403 [M+H]

Example AV6-Benzyloxy-1-[(E)-2-(2,4-dimethoxyphenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-3-(2,4-Dimethoxyphenyl)prop-2-enoic acid: A mixture of2,4-dimethoxybenzaldehyde [0.43 g (0.0026 mol)], malonic acid [0.53 g(0.0052 mol)], pyridine (5 mL) and piperidine (0.050 mL) was stirred at80° C. for 1 h followed by stirring for 3 h at 115° C. The reaction wasthen poured into water (100 mL) and acidified with conc. HCl. Theresulting white ppt., product, was filtered and vacuum dried. Yield=577mg (99%)]

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(3,4,5-trimethoxyphenyl)prop-2-enamide:To a suspension of (E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoic acid[0.577 g (0.0026 mol)] in 20 ml of Dichloromethane was added 2 drops ofDMF followed by oxalyl chloride [271 ul (3.2 mol)]. After 1 h stirringat room temperature the reaction was rotary evaporated to dryness andthe resulting yellow residue was dried in vacuo. To a solution of2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [565 mg (2.2 mmol)] and DIEA[1 mL (6 mmol)] in 20 ml of Dichloromethane was added dropwise, at icebath temperature, the crude yellow acyl chloride dissolved in 4 ml ofDichloromethane. The reaction mix was then stirred at room temperature 2h then diluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. TheEtOAc layer was dried (MgSO4) and the solvent removed. Yield=780 mg(67%) after flash with 10% MeOH/DCM)

6-Benzyloxy-1-[(E)-2-(2,4-dimethoxyphenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(2,4-dimethoxyphenyl)prop-2-enamide[780 mg (1.74 mmol)] in ACN (30 ml) was added, under reflux, POCl3 [1000ul (11 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 ml ofchloroform and was then treated with 20 ml of 2N KOH and 50 ml of Et2O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na2SO4) and thesolvent removed. The dark oil was the dissolved into 24 ml of dry MeOHand then treated with NaBH4 [60 mg (1.65 mmol)]. The mixture was stirredfor 1 h at room temperature. A light yellow solid ppt′d out of solution,was filtered off, triturated with 0.1% TFA and then dried in vacuo.Yield=22 mg (3% overall) as TFA salt. MS (m/z): 432 [M+H]

Example AW6-Benzyloxy-7-methoxy-1-[(E)-2-(4-pyridyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

(E)-3-(4-Pyridyl)prop-2-enoic acid: pyridine-4-carbaldehyde (5 g, 0.047mol), malonic acid (2.2 g (0.094 mol)), pyridine (30 mL), and piperidine(850 ul, 8.5 mmol) were mixed well, heated to 80-85° C. for 1 h andfinally refluxed (110-115° C.) for an additional 3 h. The reactionmixture was poured into water and acidified with concentrated HCl. Theprecipitate obtained was filtered, and washed with cold waterrepeatedly. The residue was dissolved in NaOH, diluted, again acidified,the precipitate was collected washed with cold water and dried underhigh vacuum over P₂O₅ and used without further purifications. Yield=6.9g.

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(4-pyridyl)prop-2-enamide:To a suspension of (E)-3-(4-pyridyl)prop-2-enoic acid [0.149 g (1 mmol)]in 10 ml of Dichloromethane was added 1 drop of DMF followed by oxalylchloride [300 ul (3 mmol)]. After 1 h stirring at room temperature thereaction was rotary evaporated to dryness and the resulting yellowresidue was dried in vacuo. To a solution of2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [257 mg (1 mmol)] and DIEA [1mL (6 mmol)] in 20 ml of Dichloromethane was added dropwise, at ice bathtemperature, the crude yellow acyl chloride dissolved in 4 ml ofDichloromethane. The reaction mix was then stirred at room temperature 2h then diluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. TheEtOAc layer was dried (MgSO4) and the solvent removed. Yield=234 mg(60%) after flash with 10% MeOH/DCM)

6-Benzyloxy-7-methoxy-1-[(E)-2-(4-pyridyl)vinyl]-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(4-pyridyl)prop-2-enamide[234 mg (0.6 mmol)] in ACN (15 ml) was added, under reflux, POCl3 [500ul (5.2 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 ml ofchloroform and was then treated with 20 ml of 2N KOH and 50 ml of Et2O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na2SO4) and thesolvent removed. The dark oil was the dissolved into 24 ml of dry MeOHand then treated with NaBH4 [5 mg (0.13 mmol)]. The mixture was stirredfor 1 h at room temperature. A light yellow solid ppt′d out of solution,was filtered off, triturated with 0.1% TFA and then dried in vacuo.Yield=130 mg (58% overall) as TFA salt. MS (m/z): 371 [M+H]

Example AX6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methoxy-3-pyridyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

(E)-3-(6-Methoxy-3-pyridyl)prop-2-enoic acid:6-methoxypyridine-3-carbaldehyde (1 g (0.007 mol)), malonic acid (1.45 g(0.014 mol)), pyridine (5 mL), and piperidine (100 ul, 1 mmol) weremixed well, heated to 80-85° C. for 1 h and finally refluxed (110-115°C.) for an additional 3 h. The reaction mixture was poured into waterand acidified with concentrated HCl. The precipitate obtained wasfiltered, and washed with cold water repeatedly. The residue wasdissolved in NaOH, diluted, again acidified, the precipitate wascollected washed with cold water and dried under high vacuum over P₂O₅and used without further purifications. Yield=950 mg.

(E)-N-[2-(3-Benzyloxy-4-methoxy-phenyl)ethyl]-3-(6-methoxy-3-pyridyl)prop-2-enamide:To a suspension of (E)-3-(6-methoxy-3-pyridyl)prop-2-enoic acid [0.179 g(1 mmol)] in 10 ml of Dichloromethane was added 1 drop of DMF followedby oxalyl chloride [300 ul (3 mmol)]. After 1 h stirring at roomtemperature the reaction was rotary evaporated to dryness and theresulting yellow residue was dried in vacuo. To a solution of2-(3-benzyloxy-4-methoxy-phenyl)ethanamine [257 mg (1 mmol)] and DIEA [1mL (6 mmol)] in 20 ml of Dichloromethane was added dropwise, at ice bathtemperature, the crude yellow acyl chloride dissolved in 4 ml ofDichloromethane. The reaction mix was then stirred at room temperature 2h then diluted with 50 mL of EtOAc and washed 2× with sat. NaCl aq. TheEtOAc layer was dried (MgSO4) and the solvent removed. Yield=395 mg(94%) after flash chromatography with 10% MeOH/DCM)

6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methoxy-3-pyridyl)vinyl]-1,2,3,4-tetrahydroisoquinoline:To a solution of(E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)ethyl]-3-(6-methoxy-3-pyridyl)prop-2-enamide[395 mg (0.94 mmol)] in ACN (45 ml) was added, under reflux, POCl3 [1500ul (16 mmol)]. The reaction was stirred at reflux for 10 min and thenrotary evaporated to dryness. The residue was taken up into 10 ml ofchloroform and was then treated with 20 ml of 2N KOH and 50 ml of Et2O.This mixture was rapidly stirred for 30 min at room temperature and theupper organic layer removed, washed with water, dried (Na2SO4) and thesolvent removed. The dark oil was the dissolved into 15 ml of dry MeOHand then treated with NaBH4 [5 mg (0.14 mmol)]. The mixture was stirredfor 1 h at room temperature. A light yellow solid ppt′d out of solution,was filtered off, triturated with 0.1% TFA and then dried in vacuo.Yield=226 mg (60% overall) as TFA salt. MS (m/z): 403 [M+H]

Example AY6-(Benzyloxy)-1-(5-(benzyloxy)-4-methoxy-2-methylphenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

1-(Benzyloxy)-2-methoxy-4-methylbenzene: 2-Methoxy-4-methylphenol (14.9g, 107.8 mmol) was combined with benzylbromide (37.2 g, 217.5 mmol),K₂CO₃ (30 g, 217.5 mmol), in acetonitrile (220 mL) and heated at refluxfor 18 hours. After TLC analysis showed complete reaction, it wasallowed to cool to room temperature. The organic solvent was evaporatedto dryness, the residue obtained was extracted with EtOAc and water. Thecombined organic layers were dried over MgSO₄, filtered and evaporatedto dryness the crude product obtained was used in the next step withoutfurther purification. LCMS: M+1=229.3.

1-(Benzyloxy)-5-bromo-2-methoxy-4-methylbenzene: The1-(Benzyloxy)-2-methoxy-4-methylbenzene (3.00 g, 13.14 mmol) wasdissolved in dry DMF (25 mL) and NBS (2.34 g, 13.14 mmol) was added inportions. The resulting reaction mixture was stirred at room temperaturefor 18 hours. The reaction was monitored by TLC analysis, uponcompletion the organic solvent was removed under high vacuum to dryness.The residue obtained was purified by flash chromatography to afford thedesired product as a solid. LCMS: M+1=308.2.

6-(Benzyloxy)-1-(5-(benzyloxy)-4-methoxy-2-methylphenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline:The 1-(Benzyloxy)-5-bromo-2-methoxy-4-methylbenzene (307 mg, 1.0 mmol)was dissolved in dry THF (10 mL) and cooled to −78° C., under argon. Tothis solution was added t-BuLi (1.3 mL, 2.2 mmol, 1.7M in pentane)dropwise, as the solution turned light yellow. After the addition, thereaction mixture was stirred for an hour at −78° C. before a solution of6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline (268 mg, 1.0 mmol) inTHF (3 mL) was added drop-wise. The mixture was allowed to stir at −78°C. for 2 hours, and then immediately quenched with sat. aqueous NH₄Clsolution. The reaction mixture was extracted with EtOAc, and thecombined organic layers were dried over MgSO₄, filtered and evaporatedto dryness. The residue obtained was purified by flash chromatography toafford the titled compound. LCMS: M+1=496.

Example AZ tert-ButylN-[[2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl]methyl]carbamate

The title compound was obtained from tert-ButylN-[(2-bromophenyl)methyl]carbamate using the same protocol as describedin Example AY above. LC-MS; M+1=475.

Example BA6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-2,6-dimethyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

2-[(E)-2-bromovinyl]-5-methoxy-1,3-dimethyl-benzene: This intermediatewas obtain first through the alternate cinnamic acid approach protocol(which utilizes ethyl 2-diethoxyphosphanylacetate) to obtain thecorresponding cinnamic acid in 2 steps. The conversion to the vinylbromide followed the same protocol as Example AD.

6-benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-2,6-dimethyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline:The title compound was obtained through the same protocol as shown inExample AD above. LC-MS; M+1=430.

Example BB6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

5-[(E)-2-bromovinyl]-6-methyl-1,3-benzodioxole was obtained from6-methyl-1,3-benzodioxole-5-carbaldehyde through the two step protocolas shown in Example AD.

6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinolinewas obtained using the same conditions as in Example AD above. LC-MS;M+1=430.

Example BC6-Benzyloxy-7-methoxy-1-[(E)-2-(7-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

6-[(E)-2-Bromovinyl]-7-methyl-2,3-dihydro-1,4-benzodioxine was obtainedfrom 7-methyl-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde using theprotocol in Example AD above.

6-Benzyloxy-7-methoxy-1-[(E)-2-(7-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)vinyl]-1,2,3,4-tetrahydroisoquinolinewas obtained using the same procedure as in Example AD above. LC-MS;M+1=444.

Example BD6-Benzyloxy-1-[(E)-2-(4-butoxy-3-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

4-[(E)-2-bromovinyl]-1-butoxy-2-methoxy-benzene was obtained from4-butoxy-3-methoxy-benzaldehyde using the two step protocol above inExample AD.

6-benzyloxy-1-[(E)-2-(4-butoxy-3-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolinewas obtained using the protocol in Example AD above. LC-MS; M+1=474.

Example BE6-Benzyloxy-1-[(E)-2-(3-butoxy-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

4-[(E)-2-bromovinyl]-2-butoxy-1-methoxy-benzene was obtained from3-butoxy-4-methoxy-benzaldehyde using the two step protocol in ExampleAD above.

6-benzyloxy-1-[(E)-2-(3-butoxy-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolinewas obtained using the same protocol as Example AD. LC-MS; M+1=474.

Example BF6-Benzyloxy-1-[(E)-2-(5-fluoro-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

4-[(E)-2-bromovinyl]-2-fluoro-1-methoxy-benzene was obtained from3-fluoro-4-methoxy-benzaldehyde using the 2 step protocol in Example ADabove.

6-benzyloxy-1-[(E)-2-(5-fluoro-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolinewas obtained using the same protocol as Example AD above. LC-MS;M+1=434.

Example BG4-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-N,N,3-trimethyl-aniline

4-[(E)-2-bromovinyl]-N,N,3-trimethyl-aniline was obtained from4-(dimethylamino)-2-methyl-benzaldehyde usingethyl-2-(diethoxyphosphino)acetate in the alternate method for thesynthesis of cinnamic acids above. The resulting cinnamic acid wasconverted to the 4-[(E)-2-bromovinyl]-N,N,3-trimethyl-aniline as inExample AD.

4-[(E)-2-(6-Benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-N,N,3-trimethyl-anilinewas obtained using the same protocol as in Example AD above. LC-MS;M+1=429

Example BH6-Benzyloxy-7-methoxy-1-[(E)-2-[2-methyl-5-(trifluoromethoxy)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline

2-[(E)-2-bromovinyl]-1-methyl-4-(trifluoromethoxy)benzene wassynthesized from 2-methyl-5-(trifluoromethoxy)benzaldehyde using the 2step protocol in Example AD.

6-Benzyloxy-7-methoxy-1-[(E)-2-[2-methyl-5-(trifluoromethoxy)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinolinewas synthesized through the same protocol as Example AD above. LC-MS;M+1=470.

Example BI6-Benzyloxy-7-methoxy-1-[(E)-styryl]-1,2,3,4-tetrahydroisoquinoline

[(E)-2-bromovinyl]benzene was obtained from benzaldehyde in the samemanner as Example AD.

6-Benzyloxy-7-methoxy-1-[(E)-styryl]-1,2,3,4-tetrahydroisoquinoline wasobtained using the same protocol as shown in Example AD. LC-MS; M+1=372.

Example BJ6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxyphenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

1-[(E)-2-bromovinyl]-4-methoxy-benzene was obtained from4-methoxybenzaldehyde in the same manner as Example AD.

6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxyphenyl)vinyl]-1,2,3,4-tetrahydroisoquinolinewas was obtained using the same protocol as shown in Example AD. LC-MS;M+1=402.

Example BK6-Benzyloxy-1-[(E)-2-(3-benzyloxyphenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

1-Benzyloxy-3-[(E)-2-bromovinyl]benzene was synthesized from3-benzyloxybenzaldehyde using the two step protocol in Example AD above.

6-Benzyloxy-1-[(E)-2-(3-benzyloxyphenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolinewas obtained using the same protocol in Example AD above. LS-MS;M+1=478.

Example BL6-Benzyloxy-1-[(E)-2-(5-butoxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

1-[(E)-2-bromovinyl]-5-butoxy-4-methoxy-2-methyl-benzene was synthesizedfrom 5-butoxy-4-methoxy-2-methyl-benzaldehyde using the 2 step protocolin Example AD above.

6-Benzyloxy-1-[(E)-2-(5-butoxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolinewas synthesized using the protocol in Example AD. LC-MS; M+1=488.

Example BM6-Benzyloxy-1-[(E)-2-(2,3-dihydrobenzofuran-5-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

5-[(E)-2-Bromovinyl]-2,3-dihydrobenzofuran was synthesized from2,3-dihydrobenzofuran-5-carbaldehyde using the 2 step protocol inExample AD.

6-Benzyloxy-1-[(E)-2-(2,3-dihydrobenzofuran-5-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolinewas synthesized using the protocol in Example AD above. LC-MS; M+1=414.

Example BN1-[(E)-2-(benzofuran-5-yl)vinyl]-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline

5-[(E)-2-bromovinyl]benzofuran was synthesized frombenzofuran-5-carbaldehyde using the two step protocol in Example ADabove.

1-[(E)-2-(benzofuran-5-yl)vinyl]-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolinewas synthesized using the protocol in Example AD above. LC-MS; M+1=412

Example BO4-[5-[(E)-2-(B-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-2-methoxy-4-methyl-phenoxy]butanoicacid

tert-Butyl 4-[5-[(E)-2-bromovinyl]-2-methoxy-4-methyl-phenoxy]butanoatewas synthesized from tert-butyl4-(5-formyl-2-methoxy-4-methyl-phenoxy)butanoate by a 2 step protocol inExample AD above.

4-[5-[(E)-2-(B-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-2-methoxy-4-methyl-phenoxy]butanoicacid was synthesized through the protocol above in Example AD. LC-MS;M−1=416

Example BP6-Benzyloxy-1-[(E)-2-(2-fluoro-4,5-dimethoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

To a solution of 1-[(E)-2-bromovinyl]-2-fluoro-4,5-dimethoxy-benzene[261mg (1 mmol)] in Ether (15 ml) at −780 C was added 1.7 M t-Butyllithium[1.2 ml (2.2 mmol)]. The mixture was stirred at −780 C for 1 h thentreated at −780 with a mix of6-benzyloxy-7-methoxy-3,4-dihydroisoquinoline [134 mg (0.5 mmol)] andTMSCl [64 ul (0.5 mmol)] in THF (2 ml). The reaction was stirred at −780C for 1 h and then allowed to come to room temperature overnight. Thereaction was then quenched with sat NH4Cl and diluted with 20 ml ofEtOAc. The organic layer was removed, washed with water, dried (MgSO4)and the solvent removed. Yield=39 mg (9%) as TFA salt via prep chrom. MS(m/z): 450 [M+H]

Example BQ6-Benzyloxy-1-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

To a solution of 1-[(E)-2-bromovinyl]-2-fluoro-4-methoxy-benzene [486 mg(0.2 mmol)] in Ether (30 ml) at −780 C was added 1.7 M t-Butyllithium[2.4 ml (4.4 mmol)]. The mixture was stirred at −780 C for 1 h thentreated at −780 with a mix of6-benzyloxy-7-methoxy-3,4-dihydroisoquinoline [267 mg (1 mmol)] andTMSCl [127 ul (1 mmol)] in THF (4 ml). The reaction was stirred at −780C for 1 h and then allowed to come to room temperature overnight. Thereaction was then quenched with sat NH4Cl and diluted with 20 ml ofEtOAc. The organic layer was removed, washed with water, dried (MgSO4)and the solvent removed. Yield=42 mg (5%) as TFA salt via prep chrom. MS(m/z): 432 [M+H]

Example BR6-Benzyloxy-1-[(E)-2-(2-fluoro-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

To a solution of 1-[(E)-2-bromovinyl]-2-fluoro-4-methoxy-benzene [462 mg(0.2 mmol)] in Ether (30 ml) at −780 C was added 1.7 M t-Butyllithium[2.4 ml (4.4 mmol)]. The mixture was stirred at −780 C for 1 h thentreated at −780 with a mix of6-benzyloxy-7-methoxy-3,4-dihydroisoquinoline [267 mg (1 mmol)] andTMSCl [127 ul (1 mmol)] in THF (4 ml). The reaction was stirred at −780C for 1 h and then allowed to come to room temperature overnight. Thereaction was then quenched with sat NH4Cl and diluted with 20 ml ofEtOAc. The organic layer was removed, washed with water, dried (MgSO4)and the solvent removed. Yield=64 mg (8%) as TFA salt via prep chrom. MS(m/z): 420 [M+H]

Example BS6-Benzyloxy-7-methoxy-1-[(E)-2-(3-methyl-2-thienyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

To a solution of 2-[(E)-2-bromovinyl]-3-methyl-thiophene [203 mg (1mmol)] in Ether (15 ml) at −780 C was added 1.7 M t-Butyllithium [1.2 ml(2.2 mmol)]. The mixture was stirred at −78° C. for 1 h then treated at−780 with a mix of 6-benzyloxy-7-methoxy-3,4-dihydroisoquinoline [134 mg(0.5 mmol)] and TMSCl [64 ul (0.5 mmol)] in THF (2 ml). The reaction wasstirred at −780 C for 1 h and then allowed to come to room temperatureovernight. The reaction was then quenched with sat NH4Cl and dilutedwith 20 ml of EtOAc. The organic layer was removed, washed with water,dried (MgSO4) and the solvent removed. Yield=15 mg (4%) as TFA salt viaprep chrom. MS (m/z): 392 [M+H]

Example BT6-Benzyloxy-1-[(E)-2-(1H-indazol-6-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

To a solution of [5-[(E)-2-bromovinyl]indazol-1-yl]-triisopropyl-silane[379 mg (1 mmol)] in Ether (15 ml) at −780 C was added 1.7 Mt-Butyllithium [1.2 ml (2.2 mmol)]. The mixture was stirred at −780 Cfor 1 h then treated at −780 with a mix of6-benzyloxy-7-methoxy-3,4-dihydroisoquinoline [134 mg (0.5 mmol)] andTMSCl [64 ul (0.5 mmol)] in THF (2 ml). The reaction was stirred at −780C for 1 h and then allowed to come to room temperature overnight. Thereaction was then quenched with sat NH4Cl and diluted with 20 ml ofEtOAc. The organic layer was removed, washed with water, dried (MgSO4)and the solvent removed. Yield=15 mg (4%) as TFA salt via prep chrom. MS(m/z): 412 [M+H]

Example BU6-Benzyloxy-1-[(E)-2-(2,6-difluoro-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

To a solution of 2-[(E)-2-bromovinyl]-1,3-difluoro-5-methoxy-benzene[248 mg (1 mmol)] in Ether (15 ml) at −780 C was added 1.7 Mt-Butyllithium [1.2 ml (2.2 mmol)]. The mixture was stirred at −78° C.for 1 h then treated at −780 with a mix of6-benzyloxy-7-methoxy-3,4-dihydroisoquinoline [134 mg (0.5 mmol)] andTMSCl [64 ul (0.5 mmol)] in THF (2 ml). The reaction was stirred at −78°C. for 1 h and then allowed to come to room temperature overnight. Thereaction was then quenched with sat NH₄Cl and diluted with 20 ml ofEtOAc. The organic layer was removed, washed with water, dried (MgSO₄)and the solvent removed. Yield=10 mg (2.3%) as TFA salt via prep chrom.MS (m/z): 249 [M+H]

Example BV6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-2,5-dimethyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and the 4-methoxy-2,5-dimethyl-benzaldehyde (125mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=430.

Example BW6-Benzyloxy-1-[(E)-2-(5-isopropyl-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 5-isopropyl-4-methoxy-2-methyl-benzaldehyde(164 mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirringunder argon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=458.

Example BX6-Benzyloxy-1-[(E)-2-[5-(2,2-dimethylpropoxy)-4-methoxy-2-methyl-phenyl]vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and5-(2,2-dimethylpropoxy)-4-methoxy-2-methyl-benzaldehyde (196 mg, 0.84mmol) in THF (10 mL) was cooled to −35° C. with stirring under argon. Tothis mixture was added a solution of lithium bis(trimethylsilyl)amide(0.68 mL, 0.68 mmol, 1M in THF) and the reaction mixture was stirred for1 hour at −35° C. The reaction was allowed to warm up to roomtemperature and the organic solvent was evaporated to give a residue.The residue was dissolved (or suspended) in 4M HCl dioxane (5 mL) andstirred at room temperature until the reaction was completed. Theorganic layer was evaporated to leave a residue, which was purified byflash or reverse phase preparatory chromatography. LC-MS; M+1=502

Example BY6-Benzyloxy-7-methoxy-1-[(E)-2-[4-methoxy-2-methyl-5-(4-piperidylmethoxy)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and isopropyl4-[(5-formyl-2-methoxy-4-methyl-phenoxy)methyl]piperidine-1-carboxylate(305 mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirringunder argon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=529

Example BZ6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methylsulfonylphenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 4-methylsulfonylbenzaldehyde (155 mg, 0.84mmol) in THF (10 mL) was cooled to −35° C. with stirring under argon. Tothis mixture was added a solution of lithium bis(trimethylsilyl)amide(0.68 mL, 0.68 mmol, 1M in THF) and the reaction mixture was stirred for1 hour at −35° C. The reaction was allowed to warm up to roomtemperature and the organic solvent was evaporated to give a residue.The residue was dissolved (or suspended) in 4M HCl dioxane (5 mL) andstirred at room temperature until the reaction was completed. Theorganic layer was evaporated to leave a residue, which was purified byflash or reverse phase preparatory chromatography. LC-MS; M+1=450.

Example CA6-Benzyloxy-1-[(E)-2-(2,6-dimethoxy-3-pyridyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 2,6-dimethoxypyridine-3-carbaldehyde (140 mg,0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=433.

Example CB6-Benzyloxy-1-[(E)-2-chroman-6-ylvinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and chromane-6-carbaldehyde (136 mg, 0.84 mmol) inTHF (10 mL) was cooled to −35° C. with stirring under argon. To thismixture was added a solution of lithium bis(trimethylsilyl)amide (0.68mL, 0.68 mmol, 1M in THF) and the reaction mixture was stirred for 1hour at −35° C. The reaction was allowed to warm up to room temperatureand the organic solvent was evaporated to give a residue. The residuewas dissolved (or suspended) in 4M HCl dioxane (5 mL) and stirred atroom temperature until the reaction was completed. The organic layer wasevaporated to leave a residue, which was purified by flash or reversephase preparatory chromatography. LC-MS; M+1=428

Example CC6-Benzyloxy-7-methoxy-1-[(E)-2-(7-methylchroman-8-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 7-methylchromane-8-carbaldehyde (148 mg, 0.84mmol) in THF (10 mL) was cooled to −35° C. with stirring under argon. Tothis mixture was added a solution of lithium bis(trimethylsilyl)amide(0.68 mL, 0.68 mmol, 1M in THF) and the reaction mixture was stirred for1 hour at −35° C. The reaction was allowed to warm up to roomtemperature and the organic solvent was evaporated to give a residue.The residue was dissolved (or suspended) in 4M HCl dioxane (5 mL) andstirred at room temperature until the reaction was completed. Theorganic layer was evaporated to leave a residue, which was purified byflash or reverse phase preparatory chromatography. LC-MS; M+1=442.

Example CD1-[(E)-2-[5-(4-azidobutoxy)-4-methoxy-2-methyl-phenyl]vinyl]-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and5-(4-azidobutoxy)-4-methoxy-2-methyl-benzaldehyde (221 mg, 0.84 mmol) inTHF (10 mL) was cooled to −35° C. with stirring under argon. To thismixture was added a solution of lithium bis(trimethylsilyl)amide (0.68mL, 0.68 mmol, 1M in THF) and the reaction mixture was stirred for 1hour at −35° C. The reaction was allowed to warm up to room temperatureand the organic solvent was evaporated to give a residue. The residuewas dissolved (or suspended) in 4M HCl dioxane (5 mL) and stirred atroom temperature until the reaction was completed. The organic layer wasevaporated to leave a residue, which was purified by flash or reversephase preparatory chromatography. LC-MS; M+1=529.

Example CE6-Benzyloxy-7-methoxy-1-[(E)-2-(7-methylchroman-6-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 7-methylchromane-6-carbaldehyde (148 mg, 0.84mmol) in THF (10 mL) was cooled to −35° C. with stirring under argon. Tothis mixture was added a solution of lithium bis(trimethylsilyl)amide(0.68 mL, 0.68 mmol, 1M in THF) and the reaction mixture was stirred for1 hour at −35° C. The reaction was allowed to warm up to roomtemperature and the organic solvent was evaporated to give a residue.The residue was dissolved (or suspended) in 4M HCl dioxane (5 mL) andstirred at room temperature until the reaction was completed. Theorganic layer was evaporated to leave a residue, which was purified byflash or reverse phase preparatory chromatography. LC-MS; M+1=442.

Example CF6-Benzyloxy-1-[(E)-2-chroman-8-ylvinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and chromane-8-carbaldehyde (136 mg, 0.84 mmol) inTHF (10 mL) was cooled to −35° C. with stirring under argon. To thismixture was added a solution of lithium bis(trimethylsilyl)amide (0.68mL, 0.68 mmol, 1M in THF) and the reaction mixture was stirred for 1hour at −35° C. The reaction was allowed to warm up to room temperatureand the organic solvent was evaporated to give a residue. The residuewas dissolved (or suspended) in 4M HCl dioxane (5 mL) and stirred atroom temperature until the reaction was completed. The organic layer wasevaporated to leave a residue, which was purified by flash or reversephase preparatory chromatography. LC-MS; M+1=428.

Example CG6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methyl-2,3-dihydrobenzofuran-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 6-methyl-2,3-dihydrobenzofuran-5-carbaldehyde(136 mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirringunder argon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=428.

Example CH tert-Butyl2-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]indole-1-carboxylate

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and tert-butyl 2-formylindole-1-carboxylate (206mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=511.

Example CI tert-Butyl3-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]indole-1-carboxylate

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and tert-butyl 3-formylindole-1-carboxylate (206mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=511

Example CJ6-Benzyloxy-1-[(E)-2-(1H-indol-3-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

The product was obtained from the reaction in Example CI. LC-MS;M+1=411.

Example CK tert-Butyl4-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)ethenyl]-1H-indole-1-carboxylate

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and tert-butyl 4-formylindole-1-carboxylate (206mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=511.

Example CL6-Benzyloxy-1-[(E)-2-(1H-indol-4-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

The product was obtained from the reaction in Example CK. LC-MS;M+1=411.

Example CM tert-Butyl5-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]indole-1-carboxylate

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and tert-butyl 5-formylindole-1-carboxylate (206mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=511.

Example CN tert-Butyl7-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]indole-1-carboxylate

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and tert-butyl 7-formylindole-1-carboxylate (206mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=511.

Example CO3-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-2,6-difluoro-phenol

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 2,4-difluoro-3-hydroxy-benzaldehyde (133 mg,0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=424.

Example CP6-Benzyloxy-7-methoxy-1-[(E)-2-(3-methylsulfonylphenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 3-methylsulfonylbenzaldehyde (155 mg, 0.84mmol) in THF (10 mL) was cooled to −35° C. with stirring under argon. Tothis mixture was added a solution of lithium bis(trimethylsilyl)amide(0.68 mL, 0.68 mmol, 1M in THF) and the reaction mixture was stirred for1 hour at −35° C. The reaction was allowed to warm up to roomtemperature and the organic solvent was evaporated to give a residue.The residue was dissolved (or suspended) in 4M HCl dioxane (5 mL) andstirred at room temperature until the reaction was completed. Theorganic layer was evaporated to leave a residue, which was purified byflash or reverse phase preparatory chromatography. LC-MS; M+1=450.

Example CQ6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methoxy-2,3-dihydro-1,4-benzodioxin-7-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and6-methoxy-2,3-dihydro-1,4-benzodioxine-7-carbaldehyde (163 mg, 0.84mmol) in THF (10 mL) was cooled to −35° C. with stirring under argon. Tothis mixture was added a solution of lithium bis(trimethylsilyl)amide(0.68 mL, 0.68 mmol, 1M in THF) and the reaction mixture was stirred for1 hour at −35° C. The reaction was allowed to warm up to roomtemperature and the organic solvent was evaporated to give a residue.The residue was dissolved (or suspended) in 4M HCl dioxane (5 mL) andstirred at room temperature until the reaction was completed. Theorganic layer was evaporated to leave a residue, which was purified byflash or reverse phase preparatory chromatography. LC-MS; M+1=460

Example CR6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methoxy-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 6-methoxy-1,3-benzodioxole-5-carbaldehyde (151mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=446.

Example CS tert-Butyl6-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]indole-1-carboxylate

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and tert-butyl 6-formylindole-1-carboxylate (206mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=511.

Example CT2-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-4,5-dimethoxy-N,N-dimethyl-aniline

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 2-(dimethylamino)-4,5-dimethoxy-benzaldehyde(176 mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirringunder argon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=475

Example CU3-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-N,N-dimethyl-pyridin-2-amine

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and 2-(dimethylamino)pyridine-3-carbaldehyde (126mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=416

Example CV Ethyl4-[5-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-2-methoxy-phenoxy]butanoate

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and ethyl 4-(5-formyl-2-methoxy-phenoxy)butanoate(223 mg, 0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirringunder argon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=532.

Example CW tert-ButylN-[2-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]phenyl]carbamate

A solution of tert-Butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate(100 mg, 0.169 mmol) and tert-butyl N-(2-formylphenyl)carbamate (186 mg,0.84 mmol) in THF (10 mL) was cooled to −35° C. with stirring underargon. To this mixture was added a solution of lithiumbis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and thereaction mixture was stirred for 1 hour at −35° C. The reaction wasallowed to warm up to room temperature and the organic solvent wasevaporated to give a residue. The residue was dissolved (or suspended)in 4M HCl dioxane (5 mL) and stirred at room temperature until thereaction was completed. The organic layer was evaporated to leave aresidue, which was purified by flash or reverse phase preparatorychromatography. LC-MS; M+1=487.

Example CX2-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]aniline

The product was obtained from the reaction in Example CW. LC-MS;M+1=387.

Example CY(E)-6-(Benzyloxy)-7-methoxy-1-(4-methoxy-3-(trifluoromethyl)styryl)-1,2,3,4-tetrahydroisoquinoline

This compound was prepared by the Methylenation reaction for aldehydesand ketones using the new Julia-Kocienski olefination reaction; (KaoriAndo et. al, Organic Letter, April, 2015); Raju Jannapu Reddy, et. al,JOC. To the solution of tert-butyl6-(benzyloxy)-7-methoxy-1-(2-phenyl-2H-tetrazol-5-ylsulfonyl)methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.2016 g, 0,340 mmol) and 4-methoxy-3-(trifluoromethyl) benzaldehyde(58 mgs, 0.284 mmol) in anhydrous DMF (5 ml) under argon was addedsodium tert-butoxide (82 mgs, 0.85 mmol) at room temperature. Afterstirring for 1 hr, the reaction was quenched with aqueous NH₄Cl and themixture was extracted with EtOAc (2×50 ml), the combined extracts werewashed with H2O, brine, dried (MgSO₄), filtered and concentrated todryness. The crude obtained was treated with 1,2-dichloroethane and 4MHCl-in-Dioxane (v/v) monitored by LCMS, upon completion, it wasconcentrated to dryness and purified by HPLC to afford the TFA salt ofthe titled compound. M+H=470.

Example CZ(E)-6-(benzyloxy)-7-methoxy-1-(4-methoxy-3-methyl-5-(trifluoromethyl)styryl)-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-7-methoxy-1-(4-methoxy-3-methyl-5-(trifluoromethyl)styryl)-1,2,3,4-tetrahydroisoquinolinewas prepared as described in detail above using4-methoxy-3-methyl-5-(trifluoromethyl)benzaldehyde (62 mgs, 0.28 mmol)to afford the titled compound. M+H=484.

Example DA(E)-6-(benzyloxy)-7-methoxy-1-(2-(trifluoromethyl)styryl)-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-7-methoxy-1-(2-(trifluoromethyl)styryl)-1,2,3,4-tetrahydroisoquinolinewas prepared as described above using 2-(trifluoromethyl)benzaldehyde(0.61 g, 0.35 mmol) to afford the titled compound. M+H=440.

Example DB(E)-6-(benzyloxy)-7-methoxy-1-(3-(trifluoromethyl)styryl)-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-7-methoxy-1-(3-(trifluoromethyl)styryl)-1,2,3,4-tetrahydroisoquinolinewas prepared using 3-(trifluoromethyl)benzaldehyde (0.61 g, 0.35 mmol)to afford the titled compound. M+H=440.

Example DC(E)-2-(2-(6-(benzyloxy)-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl)-N,N-dimethylamine

To the stirred solution of 10 (0.2578 g, 0.44 mmol) and2-(dimethylamino)benzaldehyde (0.2602 g, 1.74 mmol, 5 eq.) in anhydrousTHF (10 ml), under argon at −35° C. was added sodiumbis(trimethylsilyl)amide (1.0M in THF, 1.7 ml) dropwise. The resultingpale yellow solution was stirred vigorously for an additional 1 hr anddiluted with sat. ammonium chloride, and the mixture was extracted withethyl acetate. The organic layer was washed with water, brine, dried(MgSO4), filtered, concentrated to dryness, residue obtained subjectedto boc-deprotection using 4M HCl-in-Dioxane and 1,2-Dichloroethane. Thecrude after concentration was purified by the Waters LCMS prepsystem toafford the titled compound as the TFA salt. M+H=415.

Example DD(E)-(benzyloxy)-7-methoxy-1-(2-(2-methoxypyrimidin-5-yl)vinyl)-1,2,3,4-tetrahydroisoquinoline

(E)-(Benzyloxy)-7-methoxy-1-(2-(2-methoxypyrimidin-5-yl)vinyl)-1,2,3,4-tetrahydroisoquinolinewas prepared as described above using 2-methoxypyrimidine-5-carbaldehyde(0.1940 g, 1.40 mmol) to afford the titled compound. M+H=404.

Example DE(E)-6-(benzyloxy)-7-methoxy-1-(2-(2-methoxyethoxy)styryl)-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-7-methoxy-1-(2-(2-methoxyethoxy)styryl)-1,2,3,4-tetrahydroisoquinolinewas prepared using 2-(2-methoxyethoxy)benzaldehyde (0.2776 g, 1.54 mmol)to afford the titled compound as the TFA salt. M+H=446.

Example DF(E)-6-(benzyloxy)-1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)vinyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)vinyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolinewas prepared using 2,2-difluorobenzo[d][1,3]dioxol-5-carbaldehyde(0.2444 g, 1.31 mmol) to afford the titled compound. M+H=452.

Example DG(E)-6-(benzyloxy)-7-methoxy-1-(2-methoxystyryl)-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-7-methoxy-1-(2-methoxystyryl)-1,2,3,4-tetrahydroisoquinolinewas prepared using 2-methoxybenzaldehyde (0.1985 g, 1.46 mmol) to affordthe titled compound. M+H=402.

Example DH(E)-4-(2-(2-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl)phenyl)morpholine

(E)-4-(2-(2-(6-(Benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl)phenyl)morpholinewas prepared using 2-morpholinobenzaldehyde (0.2218 g, 1.16 mmol) toafford the titled compound. M+H=457.

Example DI(E)-6-(benzyloxy)-7-methoxy-1-(2-(6-methoxynaphthalen-2-yl)vinyl)-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-7-methoxy-1-(2-(6-methoxynaphthalen-2-yl)vinyl)-1,2,3,4-tetrahydroisoquinolinewas prepared using 6-methoxy-2-naphthaldehyde (0.2063 g, 1.11 mmol) toafford the titled compound. M+H=452

Example DJ(E)-6-(benzyloxy-7-methoxy-1-(4-(pyridine-3-yl)styryl)-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy-7-methoxy-1-(4-(pyridine-3-yl)styryl)-1,2,3,4-tetrahydroisoquinolinewas prepared using 4-(pyridine-3-yl)benzaldehyde (0.2201 g, 1.201 mmol)to afford the titled compound.

Example DK(E)-1-(4-(1H-imidazol-1-yl)styryl)-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-1-(4-(1H-Imidazol-1-yl)styryl)-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolinewas prepared using 4-(1H-imidazol-1-yl)benzaldehyde 23 (0.2536 g, 1.5mmol) to afford the titled compound.

Example DL(E)-7-(2-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl)quinoline

(E)-7-(2-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl)quinolinewas prepared using quinolone-6-carbaldehyde (0.2789 g, 1.8 mmol) toafford the titled compound. M+H=423

Example DM(E)-6-(benzyloxy)-7-methoxy-1-(4-(2-methyl-1H-imidazol-1-yl)styryl)-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-7-methoxy-1-(4-(2-methyl-1H-imidazol-1-yl)styryl)-1,2,3,4-tetrahydroisoquinolinewas prepared using 4-(2-methyl-1H-imidazol-1-yl)benzaldehyde (0.3112 g,1.67 mmol) to afford the titled compound. M+H=452.

Example DN(E)-6-(benzyloxy)-7-methoxy-1-(2-(2-(3-methoxyphenyl)pyrimidin-5-yl)vinyl-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-7-methoxy-1-(2-(2-(3-methoxyphenyl)pyrimidin-5-yl)vinyl-1,2,3,4-tetrahydroisoquinolinewas prepared using 2-(3-methoxyphenyl)pyrimidine-5-carbaldehyde (0.2996g, 1.40 mmol) to afford the titled compound. M+H=480.

Example DO(E)-6-(benzyloxy)-1-(4-(4-ethylpiperazin-1-yl)styryl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(E)-6-(Benzyloxy)-1-(4-(4-ethylpiperazin-1-yl)styryl)-7-methoxy-1,2,3,4-tetrahydroisoquinolinewas prepared using 4-(4-ethylpiperazin-1-yl)benzaldehyde (0.3742 g, 1.71mmol) to afford the titled compound. M+H=484.

Example DP6-(Benzyloxy)-7-methoxy-1-[(E)-2-{1-methyl-1H-pyrrolo[1,2,3-b]pyridin-3-yl}ethenyl]-1,2,3,4-tetrahydroisoquinoline

To a solution of tert-butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate[118 mg (0.2 mmol)] in THF (5 ml) with1-methylpyrrolo[2,3-b]pyridine-3-carbaldehyde [96 mg (0.6 mmol)] wasadded at −38° C. 1M LiN(TMSi)₂ [600 ul (0.6 mmol)]. The reaction wasstirred at −38° C. for 60 min and then at room temperature for 30 minlonger. The reaction was quenched with sat NH₄Cl (10 ml), extracted withEtOAc (20 ml), dried (MgSO₄) and the solvent removed. The residue wastreated with 2 ml of 4NHCl in dioxane for 1 h, rotary evaporated todryness and chromatographed via reverse phase chromatography. Yield=3 mg(3.5%) as TFA salt via prep chrom. MS (m/z): 426 [M+H]

Example DQ6-(Benzyloxy)-7-methoxy-1-[(E)-2-[3-(pyridin-4-yl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 3-(4-pyridyl)benzaldehyde the reaction afforded the desiredadduct. Yield=18 mg (20%) as TFA salt via prep chrom. MS (m/z): 449[M+H]

Example DR6-(Benzyloxy)-7-methoxy-1-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde thiazole-4-carbaldehyde the reaction afforded the desiredadduct.

Yield=11 mg (14%) as TFA salt via prep chrom. MS (m/z): 379 [M+H]

Example DS6-(Benzyloxy)-7-methoxy-1-[(E)-2-[4-(pyrimidin-5-yl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-pyrimidin-5-ylbenzaldehyde the reaction afforded thedesired adduct. Yield=10 mg (11%) as TFA salt via prep chrom. MS (m/z):450 [M+H]

Example DT6-(Benzyloxy)-7-methoxy-1-[(E)-2-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-(1,2,4-triazol-1-yl)benzaldehyde the reaction affordedthe desired adduct. Yield=10 mg (11%) as TFA salt via prep chrom. MS(m/z): 439 [M+H]

Example DU1-[(E)-2-(1-Benzothiophen-2-yl)ethenyl]-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde benzothiophene-2-carbaldehyde the reaction afforded thedesired adduct. Yield=17 mg (20%) as TFA salt via prep chrom. MS (m/z):428 [M+H]

Example DV6-(Benzyloxy)-7-methoxy-1-[(E)-2-(1,3-thiazol-2-yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde thiazole-2-carbaldehyde the reaction afforded the desiredadduct.

Yield=15 mg (20%) as TFA salt via prep chrom. MS (m/z): 379 [M+H]

Example DW6-(Benzyloxy)-7-methoxy-1-[(E)-2-[4-(4-methylpiperazin-1-yl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-(4-methylpiperazin-1-yl)benzaldehyde the reactionafforded the desired adduct. Yield=3.3 mg (4%) as TFA salt via prepchrom. MS (m/z): 470 [M+H]

Example DX6-(Benzyloxy)-7-methoxy-1-[(E)-2-[2-(piperidin-1-yl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 2-(1-piperidyl)benzaldehyde the reaction afforded thedesired adduct. Yield=11 mg (12%) as TFA salt via prep chrom. MS (m/z):455 [M+H]

Example DY5-[(E)-2-(6-Benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-4-methyl-thiazole

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-methylthiazole-5-carbaldehyde the reaction afforded thedesired adduct. Yield=8 mg (10%) as TFA salt via prep chrom. MS (m/z):393 [M+H]

Example DZ6-Benzyloxy-7-methoxy-1-[(E)-2-[4-(2-pyridyl)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-(2-pyridyl)benzaldehyde the reaction afforded the desiredadduct. Yield=10 mg (11%) as TFA salt via prep chrom. MS (m/z): 449[M+H]

Example EA6-Benzyloxy-7-methoxy-1-[(E)-2-[4-(1-piperidyl)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-(1-piperidyl)benzaldehyde the reaction afforded thedesired adduct. Yield=5 mg (6%) as TFA salt via prep chrom. MS (m/z):455 [M+H]

Example EB6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methoxybenzofuran-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 6-methoxybenzofuran-5-carbaldehyde the reaction affordedthe desired adduct. Yield=20 mg (23%) as TFA salt via prep chrom. MS(m/z): 442 [M+H]

Example EC2-[3-[(E)-2-(6-Benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]phenyl]oxazole

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 3-oxazol-2-ylbenzaldehyde the reaction afforded the desiredadduct. Yield=20 mg (23%) as TFA salt via prep chrom. MS (m/z): 439[M+H]

Example ED2-[4-[(E)-2-(6-Benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]phenyl]oxazole

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-oxazol-2-ylbenzaldehyde the reaction afforded the desiredadduct. Yield=10 mg (11%) as TFA salt via prep chrom. MS (m/z): 439[M+H]

Example EE Ethyl2-[4-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]phenyl]oxazole-4-carboxylate

Using the same procedure outlined in Example DP at the same scale withthe aldehyde ethyl 2-(4-formylphenyl)oxazole-4-carboxylate the reactionafforded the desired adduct. Yield=20 mg (20%) as TFA salt via prepchrom. MS (m/z): 511 [M+H]

Example EF Ethyl2-[3-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]phenyl]oxazole-4-carboxylate

Using the same procedure outlined in Example DP at the same scale withthe aldehyde ethyl 2-(3-formylphenyl)oxazole-4-carboxylate the reactionafforded the desired adduct. Yield=25 mg (24%) as TFA salt via prepchrom. MS (m/z): 511 [M+H]

Example EG6-Benzyloxy-1-[(E)-2-(2,3-dihydrobenzofuran-6-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 2,3-dihydrobenzofuran-6-carbaldehyde the reaction affordedthe desired adduct. Yield=25 mg (30%) as TFA salt via prep chrom. MS(m/z): 414 [M+H]

Example EH6-Benzyloxy-1-[(E)-2-(2,4-dimethoxy-5-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

To a solution of tert-butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate[118 mg (0.2 mmol)] in THF (5 ml) with2,4-dimethoxy-5-methyl-benzaldehyde [36 mg (0.2 mmol)] was added at roomtemperature Na t-butoxide [58 mg (0.6 mmol)]. The reaction was stirredat room temperature for 60 min. The reaction was quenched with sat NH₄Cl(10 ml), extracted with EtOAc (20 ml), dried (MgSO₄) and the solventremoved. The residue was treated for 1 h with 3NHCl/EtOAc at roomtemperature then rotary evaporated to a brown oil which was taken upinto EtOAc and washed with 2N NaOH. The organic layer was dried (MgSO₄)and the solvent removed. The residue was chromatographed via reversephase chromatography. Yield=3.1 mg (3.5%) as TFA salt via prep chrom. MS(m/z): 446 [M+H]

Example EI6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-3-methyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

To a solution of tert-butyl6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate[118 mg (0.2 mmol)] in THF (5 ml) with 4-methoxy-3-methyl-benzaldehyde[30 mg (0.2 mmol)] was added at room temperature Na t-butoxide [58 mg(0.6 mmol)]. The reaction was stirred at room temperature for 60 min.The reaction was quenched with sat NH₄Cl (10 ml), extracted with EtOAc(20 ml), dried (MgSO4) and the solvent removed. The residue was treatedfor 1 h with 3NHCl/EtOAc at room temperature then rotary evaporated to abrown oil which was taken up into EtOAc and washed with 2N NaOH. Theorganic layer was dried (MgSO₄) and the solvent removed. The residue waschromatographed via reverse phase chromatography. Yield=7.2 mg (9%) asTFA salt via prep chrom. MS (m/z): 416 [M+H]

Example EJ6-Benzyloxy-7-methoxy-1-[(E)-2-(3-methoxyphenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 3-methoxybenzaldehyde the reaction afforded the desiredadduct.

Yield=37 mg (45%) as TFA salt via prep chrom. MS (m/z): 402 [M+H]

Example EK6-Benzyloxy-1-[(E)-2-(2,5-dimethoxyphenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 2,5-dimethoxybenzaldehyde the reaction afforded the desiredadduct.

Yield=50 mg (57%) as TFA salt via prep chrom. MS (m/z): 432 [M+H]

Example EL6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-2,3-dimethyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-methoxy-2,3-dimethyl-benzaldehyde the reaction affordedthe desired adduct. Yield=20 mg (23%) as TFA salt via prep chrom. MS(m/z): 430 [M+H]

Example EM6-Benzyloxy-7-methoxy-1-[(E)-2-[4-methoxy-3-(1-piperidylmethyl)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-methoxy-2,3-dimethyl-benzaldehyde the reaction affordedthe desired adduct. Yield=10 mg (10%) as TFA salt via prep chrom. MS(m/z): 499 [M+H]

Example EN6-Benzyloxy-7-methoxy-1-[(E)-2-[4-methoxy-3-[(2-methylimidazol-1-yl)methyl]phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-methoxy-3-[(2-methylimidazol-1-yl)methyl]benzaldehyde thereaction afforded the desired adduct. Yield=8.2 mg (8%) as TFA salt viaprep chrom. MS (m/z): 496 [M+H]

Example EO6-Benzyloxy-7-methoxy-1-[(E)-2-[4-methoxy-3-(2,2,2-trifluoroethoxymethyl)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-methoxy-3-(2,2,2-trifluoroethoxymethyl)benzaldehyde thereaction afforded the desired adduct. Yield=9 mg (9%) as TFA salt viaprep chrom. MS (m/z): 514 [M+H]

Example EP(E)-6-(benzyloxy)-1-(3-(ethoxymethyl)-4-methoxystyryl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-methoxy-3-(methoxymethyl)benzaldehyde the reactionafforded the desired adduct. Yield=11 mg (10%) as TFA salt via prepchrom. MS (m/z): 460 [M+H]

Example EQ4-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]benzoicacid

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-formylbenzoic acid the reaction afforded the desiredadduct. Yield=11 mg (13%) as TFA salt via prep chrom. MS (m/z): 416[M+H]

Example ER3-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]benzoicacid

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 3-formylbenzoic acid the reaction afforded the desiredadduct. Yield=21 mg (25%) as TFA salt via prep chrom. MS (m/z): 416[M+H]

Example ES2-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]benzoicacid

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 2-formylbenzoic acid the reaction afforded the desiredadduct. Yield=2.6 mg (3% overall) as TFA salt via prep chrom. MS (m/z):416 [M+H]

Example ET Ethyl2-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]benzoate

Using the same procedure outlined in Example DP at the same scale withthe aldehyde ethyl 2-formylbenzoate the reaction afforded the desiredadduct. Yield=11.7 mg (13% overall) as TFA salt via prep chrom. MS(m/z): 444 [M+H]

Example EU6-Benzyloxy-7-methoxy-1-[(E)-2-[4-methoxy-3-(phenoxymethyl)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline

Using the same procedure outlined in Example DP at the same scale withthe aldehyde 4-methoxy-3-(phenoxymethyl)benzaldehyde the reactionafforded the desired adduct. Yield=7.3 mg (6% overall) as TFA salt viaprep chrom. MS (m/z): 508 [M+H]

Data for Biological Examples Protocol for MT-2 Spread Assay

The present assay was used to screen candidate antiviral compounds byquantification of virus spread and production over several rounds ofinfection in vitro. MT-2, a HIV-1 permissive human T-cell line, wasseeded in microtiter plates and was simultaneously treated with seriallydiluted compound and inoculated with a HIV-1 NL4-3 viral cloneengineered to express Renilla luciferase in place of Net Followingtreatment, the culture was incubated for 96 hours. After the incubation,media was collected and used to estimate relative infectivity on theindicator cell line, TZM-bl. Additionally, viral spread was quantifiedby measuring luciferase activity via a commercially available luciferasesubstrate. In parallel, MT-2 cells were seeded and inoculated with mockvirus in the presence of serially diluted compound. Compound toxicitywas quantified 96 hours after treatment with AlamarBlue.

Compound Treatment and Infection:

MT-2 (NIH Aids reagent program 237) cells were grown and maintained inan incubator at 37° C. with 5% CO₂ using a basal medium of RPMI-1640supplemented with 10% FBS. Cells were seeded in 100 μl at 2×10⁴cells/well in white walled 96-well microtiter plates. Candidatecompounds were 3-fold serially diluted in the appropriate solvent.Solvent without compound was used as a no drug reference. Cells wereinoculated at a multiplicity of 0.027 with an HIV-1 NL4-3 virus stockengineered to express Renilla luciferase in place of Net Diluted virusstock was first added to serially diluted compound. Compound and viruswere delivered to cells in an equal volume (100 μl) and treated cultureswere returned to the incubator for 96 hours. In parallel, plates forcytotoxicity estimates were prepared in the same way except cells wereplated in clear walled 96-well microtiter plates and were mock infected.

Infectivity Assay:

At 96 hours post infection, 100 μl virus containing culture supernatantwas collected from the treated and infected cultures and seriallydiluted in DMEM supplemented with 10% FBS, 1% sodium pyruvate, and 20μg/ml DEAE dextran. One day prior, TZM-bl (ATCC PTA-5659) were culturedin basal medium of DMEM supplemented with 10% FBS and 1% sodium pyruvateand seeded at 7.5×10³ cells/well in black walled 96-well microtiterplates. Diluted virus containing culture supernatant was transferred toTZM-bl cultures and incubated for 48 hours at 37° C. with 5% CO₂.Infected TZM-bl cultures were fixed for 5 minutes with a 1%formaldehyde/0.2% gluteraldehyde/PBS solution then washed three timeswith PBS. Fixed cultures were incubated at 37° C. for 25 minutes with a200 μg/ml MUG (4-Methylumbelliferyl β-D-glucopyranoside)/DMEM solution.The reaction was stopped with an equal volume of 1M sodium carbonate andread at 360, 449 nm on fluorescence plate reader (Biotek).

(Viral Spread) Luciferase Assay:

At 96 hours post infection, 100 μl of culture supernatant was removedfrom the treated and infected cultures and EnduRen live cell substrate(Promega) was added at a final concentration 1.3 μg/ml. Cells wereincubated for 1.5 hours at 37° C. with 5% CO₂ then read on aluminescence plate reader (Biotek).

Cytotoxicity Assay:

At 96 hours post treatment, 20 μl AlamarBlue proliferation reagent wasadded to 200 μl treated and mock infected cultures and incubated for 3hours at 37° C. with 5% CO₂ then read at 545, 590 nm on fluorescenceplate reader (Biotek).

Analysis:

For all assays, data was imported into Accelrys Assay Explorer 3.3. InAssay Explorer, % inhibition (antiviral or cytotoxicity) was calculatedusing the solvent control as a reference by the following equation:1−(Signal_(Compound)/Signal_(Reference)). The % Inhibition and compoundconcentration data was fitted using the following 4-parameter logisticmodel (Assay Explorer model 42):

$Y = {D + \left( \frac{A - D}{1 + \left( \frac{X}{C} \right)^{B}} \right)}$

where X is compound concentration, Y is % inhibition, D is the maximum %Inhibition (constrained to 100%), C is IC50 value or inflection point, Bis the hill slope, and A is the minimum % inhibition (constrained to0%). The IC50 value is reported as the EC50 or CC50 depending on theassay endpoint. EC50 represents the effective concentration at whichvirus replication is inhibited by 50 percent. CC50 represents theconcentration that results in the death of 50 percent of the host cells.The selectivity or therapeutic index (SI or TI), is the ratio of CC50over EC50 and represents the relative effectiveness in inhibiting viralreplication compared to inducing cell death.

TABLE Code Structure Name EC₅₀, μM CC₅₀, μM SI A1-[2-(3,4-dimethoxyphenyl)ethyl]- 10 >10 1 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline B [6-benzyloxy-1-[(E)-2-(3- 10 5 0.5benzyloxy-4-methoxy- phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]- pyrazin-2-yl-methanone C1-[(E)-2-(5-benzyloxy-4-methoxy- 9.76 10.96 1.12-methyl-phenyl)vinyl]-6,7- dimethoxy-1,2,3,4- tetrahydroisoquinoline D7-benzyloxy-1-[(E)-2-(4-benzyloxy- 8.92 >10 >1.13-methoxy-phenyl)vinyl]-2-butyl-6- methoxy-3,4-dihydro-1H- isoquinolineE 6-benzyloxy-1-[(E)-2-(5-benzyloxy- 8.47 7.17 0.84-methoxy-2-methyl-phenyl)vinyl]- 7-methoxy-2-methyl-3,4-dihydro-1H-isoquinoline F (6-amino-2-pyridyl)-[6-benzyloxy- 5.05 100 19.81-[(E)-2-(5-benzyloxy-4-methoxy- 2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2- yl]methanone G6-benzyloxy-1-[(E)-2-(3-benzyloxy- 5 5 14-methoxy-phenyl)vinyl]-2-butyl-7- methoxy-3,4-dihydro-1H- isoquinolineH [6-benzyloxy-1-[(E)-2-(5- 4.48 100 22.3 benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4- dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl-methanone I methyl 6-benzyloxy-1-[(E)-2-(4,5- 4.48 100 22.3dimethoxy-2-methyl-phenyl)vinyl]- 7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate J 6-benzyloxy-1-[(E)-2-(5-benzyloxy- 4.225.36 1.27 2-tert-butyl-4-methoxy- phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline K (2-amino-3-pyridyl)-[6-benzyloxy- 2.88 10034.72 1-[(E)-2-(5-benzyloxy-4-methoxy- 2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2- yl]methanone L methyl6-benzyloxy-1-[(E)-2-(3- 2.81 >20 7.11 benzyloxy-4-methoxy-phenyl)vinyl]-7-methoxy-3,4- dihydro-1H-isoquinoline-2- carboxylate M[6-benzyloxy-1-[(E)-2-(5- 2.09 100 47.8 benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4- dihydro-1H-isoquinolin-2-yl]-(2-pyridyl)methanone N (2-amino-4-pyridyl)-[6-benzyloxy- 2.03 100 49.31-[(E)-2-(5-benzyloxy-4-methoxy- 2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2- yl]methanone O6-benzyloxy-1-[(E)-2-(5-benzyloxy- 2.011 >10 >54-methoxy-2-methyl-phenyl)vinyl]- N-tert-butyl-7-methoxy-3,4-dihydro-1H-isoquinoline-2- carboxamide P(6-amino-3-pyridyl)-[6-benzyloxy- 1.69 100 59.171-[(E)-2-(5-benzyloxy-4-methoxy- 2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2- yl]methanone Q6-benzyloxy-1-[2-(5-benzyloxy-4- 1.36 5.15 3.8methoxy-2-methyl-phenyl)ethyl]-7- methoxy-1,2,3,4-tetrahydroisoquinoline R 6-benzyloxy-1-[(E)-2-(5-benzyloxy- 1.18 39.3133.1 4-methoxy-2-methyl-phenyl)vinyl]- 7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxamide S 7-benzyloxy-1-[(E)-2-(4-benzyloxy- 0.9928.25 8.3 3-methoxy-phenyl)vinyl]-6- methoxy-1,2,3,4-tetrahydroisoquinoline T [6-benzyloxy-1-[(E)-2-(5- 0.93 100 107benzyloxy-4-methoxy-2-methyl- phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-(3- pyridyl)methanone U[6-benzyloxy-1-[(E)-2-(5- 0.87 >100 >115 benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4- dihydro-1H-isoquinolin-2-yl]-(4-pyridyl)methanone V 6-benzyloxy-1-[(E)-2-(3-benzyloxy- 0.78 6.68 8.54-methoxy-phenyl)vinyl]-7- methoxy-2-methyl-3,4-dihydro-1H- isoquinolineW 6-benzyloxy-7-methoxy-1-[(E)-2- 0.69 4 5.8 (o-tolyl)vinyl]-1,2,3,4-tetrahydroisoquinoline X 6-benzyloxy-1-[(E)-2-(4-fluoro-2- 0.62 5.3 8.53methyl-phenyl)vinyl]-7-methoxy- 1,2,3,4-tetrahydroisoquinoline Ytert-butyl 6-benzyloxy-1-[(E)-2-(5- 0.39 28.1 71.2benzyloxy-4-methoxy-2-methyl- phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinoline-2- carboxylate Z 6-benzyloxy-7-methoxy-1-[(E)-2-0.35 100 17.1 [4-methoxy-2- (trifluoromethyl)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline AA 6-benzyloxy-1-[(E)-2-(5-benzyloxy-0.148 3.89 26.3 2-ethyl-4-methoxy-phenyl)vinyl]-7- methoxy-1,2,3,4-tetrahydroisoquinoline AB 6-benzyloxy-1-[(E)-2-(3-benzyloxy- 0.146 3.9627.1 4-methoxy-phenyl)vinyl]-7- methoxy-1,2,3,4- tetrahydroisoquinolineAC 6-benzyloxy-1-[(E)-2-(5-benzyloxy- 0.0872 1.8993 21.82-chloro-4-methoxy-phenyl)vinyl]- 7-methoxy-1,2,3,4-tetrahydroisoquinoline AD 6-benzyloxy-1-[(E)-2-(5-benzyloxy- 0.084 3.2238.1 2-methyl-phenyl)vinyl]-7-methoxy- 1,2,3,4-tetrahydroisoquinoline AE6-benzyloxy-1-[(E)-2-(5-benzyloxy- 0.44 33.53 76.54-methoxy-2-methyl-phenyl)vinyl]- 7-methoxy-3,4-dihydroisoquinoline AF6-benzyloxy-1-[(E)-2-(5-benzyloxy- 0.083 3.873 48.24-methoxy-2-methyl-phenyl)vinyl]- 7-methoxy-1,2,3,4-tetrahydroisoquinoline AG 6-benzyloxy-7-methoxy-1-[(E)-2- 0.0771 9.83127.4 (4-methoxy-2-methyl-phenyl)vinyl]- 1,2,3,4-tetrahydroisoquinolineAH 6-benzyloxy-1-[(E)-2-(4,5- 0.0133 2.404 180.8dimethoxy-2-methyl-phenyl)vinyl]- 7-methoxy-1,2,3,4-tetrahydroisoquinoline AI 6-(benzyloxy)-7-methoxy-1-[(E)-2- 1.5 5.6 3.9[4-methoxy-2-(4- methoxybutoxy)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline AJ 6-(benzyloxy)-7-methoxy-1-[(E)-2- 2.745 1.83 [2-methyl-4- (trifluoromethoxy)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline AK 6-(benzyloxy)-7-methoxy-1-[(E)-2- 8.8710 1.1 (1-methyl-1H-pyrazol-5-yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline AL 6-(benzyloxy)-1-[(E)-2-(1-ethyl-1H-2.95 24.2 8.2 pyrazol-4-yl)ethenyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline AM 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.226 27.3 (3,4,5-trimethoxyphenyl)ethenyl]- 1,2,3,4-tetrahydroisoquinolineAN 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.14 3.7 26.8(7-methoxy-1-benzofuran-4- yl)ethenyl]-1,2,3,4- tetrahydroisoquinolineAO 6-(benzyloxy)-7-methoxy-1-[(E)-2- 1.13 9.94 8.8(4-methoxy-1-benzofuran-7- yl)ethenyl]-1,2,3,4- tetrahydroisoquinolineAP 6-(benzyloxy)-1-[(E)-2-[4- 0.97 1.64 1.7 (benzyloxy)-3,5-dimethoxyphenyl]ethenyl]-7- methoxy-1,2,3,4- tetrahydroisoquinoline AQ6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.0151 1.98 131.1(2,4,5-trimethoxyphenyl)ethenyl]- 1,2,3,4-tetrahydroisoquinoline AR6-(benzyloxy)-1-[(E)-2-(3-bromo-4- 0.8 6.2 8.2 methoxyphenyl)ethenyl]-7-methoxy-1,2,3,4- tetrahydroisoquinoline AS 6-(benzyloxy)-1-[(E)-2-[5-4.22 5.36 1.3 (benzyloxy)-2-tert-butyl-4- methoxyphenyl]ethenyl]-7-methoxy-1,2,3,4- tetrahydroisoquinoline AT 6-(benzyloxy)-1-[(E)-2-(3,5-0.77 4.85 6.3 dimethoxyphenyl)ethenyl]-7- methoxy-1,2,3,4-tetrahydroisoquinoline AU 6-benzyloxy-7-methoxy-1-[(E)-2- 1.65 3.22 2(2-methoxy-4-pyridyl)vinyl]-1,2,3,4- tetrahydroisoquinoline AV6-(benzyloxy)-1-[(E)-2-(2,4- 0.14 5.5 39.3 dimethoxyphenyl)ethenyl]-7-methoxy-1,2,3,4- tetrahydroisoquinoline AW6-(benzyloxy)-7-methoxy-1-[(E)-2- 3.28 11.36 3.5(pyridin-4-yl)ethenyl]-1,2,3,4- tetrahydroisoquinoline AX6-benzyloxy-7-methoxy-1-[(E)-2- 3.28 11.36 3.5(6-methoxy-3-pyridyl)vinyl]-1,2,3,4- tetrahydroisoquinoline AY6-(benzyloxy)-1-[5-(benzyloxy)-4- 4.88 5.14 1.1methoxy-2-methylphenyl]-7- methoxy-1,2,3,4- tetrahydroisoquinoline AZtert-butyl N-({2-[6-(benzyloxy)-7- 2.77 9.48 12.3 methoxy-1,2,3,4-tetrahydroisoquinolin-1- yl]phenyl}methyl)carbamate BA6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.497 3.33 6.7 (4-methoxy-2,6-dimethylphenyl)ethenyl]-1,2,3,4- tetrahydroisoquinoline BB6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.0544 2.98 54.9(6-methyl-2H-1,3-benzodioxol-5- yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline BC 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.0271 2.4390.6 (7-methyl-2,3-dihydro-1,4- benzodioxin-6-yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline BD 6-(benzyloxy)-1-[(E)-2-(4-butoxy-3- 0.408 3.628.9 methoxyphenyl)ethenyl]-7- methoxy-1,2,3,4- tetrahydroisoquinoline BE6-(benzyloxy)-1-[(E)-2-(3-butoxy-4- 0.0998 3.75 37.6methoxyphenyl)ethenyl]-7- methoxy-1,2,3,4- tetrahydroisoquinoline BF6-(benzyloxy)-1-[(E)-2-(3-fluoro-4- 1.02 33.507 32.85methoxyphenyl)ethenyl]-7- methoxy-1,2,3,4- tetrahydroisoquinoline BG4-[(E)-2-[6-(benzyloxy)-7-methoxy- 1.65 4.44 2.691,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]-N,N,3-trimethylaniline BH6-(benzyloxy)-7-methoxy-1-[(E)-2- 1.93 5.3 2.75 [2-methyl-5-(trifluoromethoxy)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline BI6-(benzyloxy)-7-methoxy-1-[(E)-2- 2.2 10 4.5 phenylethenyl]-1,2,3,4-tetrahydroisoquinoline BJ 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.477 20.90143.54 (4-methoxyphenyl)ethenyl]- 1,2,3,4-tetrahydroisoquinoline BK6-(benzyloxy)-1-[(E)-2-[3- 0.26 4 15.4 (benzyloxy)phenyl]ethenyl]-7-methoxy-1,2,3,4- tetrahydroisoquinoline BL6-(benzyloxy)-1-[(E)-2-(5-butoxy-4- 0.052 1.1 21.2methoxy-2-methylphenyl)ethenyl]- 7-methoxy-1,2,3,4-tetrahydroisoquinoline BM 6-(benzyloxy)-1-[(E)-2-(2,3- 0.146 20.43 139.8dihydro-1-benzofuran-5- yl)ethenyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline BN 1-[(E)-2-(1-benzofuran-5- 0.84 20.65 24.8yl)ethenyl]-6-(benzyloxy)-7- methoxy-1,2,3,4- tetrahydroisoquinoline BO4-{5-[(E)-2-[6-(benzyloxy)-7- 0.234 8.96 38.3 methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]ethenyl]- 2-methoxy-4- methylphenoxy}butanoicacid BP 6-(benzyloxy)-1-[(E)-2-(2-fluoro- 2.03 5.61 2.764,5-dimethoxyphenyl)ethenyl]-7- methoxy-1,2,3,4- tetrahydroisoquinolineBQ 6-(benzyloxy)-1-[(E)-2-(3,4- 0.198 8.7 43.5dimethoxyphenyl)ethenyl]-7- methoxy-1,2,3,4- tetrahydroisoquinoline BR6-(benzyloxy)-1-[(E)-2-(2-fluoro-4- 1.14 10 8.77methoxyphenyl)ethenyl]-7- methoxy-1,2,3,4- tetrahydroisoquinoline BS6-(benzyloxy)-7-methoxy-1-[(E)-2- 2.87 11.31 3.94(3-methylthiophen-2-yl)ethenyl]- 1,2,3,4-tetrahydroisoquinoline BT6-(benzyloxy)-1-[(E)-2-(1H- 0.613 7.98 13.02indazol-6-yl)ethenyl]-7-methoxy- 1,2,3,4-tetrahydroisoquinoline BU6-(benzyloxy)-1-[(E)-2-(2,6- 1.02 10.56 10.4difluoro-4-methoxyphenyl)ethenyl]- 7-methoxy-1,2,3,4-tetrahydroisoquinoline BV 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.304 2.638.7 (4-methoxy-2,5- dimethylphenyl)ethenyl]-1,2,3,4-tetrahydroisoquinoline BW 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.84 1.882.2 [4-methoxy-2-methyl-5-(propan-2- yl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline BX 6-(benzyloxy)-1-[(E)-2-[5-(2,2- 0.35 3.4 9.71dimethylpropoxy)-4-methoxy-2- methylphenyl]ethenyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline BY 6-(benzyloxy)-7-methoxy-1-[(E)-2-0.397 1.97 5 [4-methoxy-2-methyl-5-(piperidin-4-ylmethoxy)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline BZ6-(benzyloxy)-1-[(E)-2-(4- 1 1 1 methanesulfonylphenyl)ethenyl]-7-methoxy-1,2,3,4- tetrahydroisoquinoline CA 6-(benzyloxy)-1-[(E)-2-(2,6-0.64 15.3 23.9 dimethoxypyridin-3-yl)ethenyl]-7- methoxy-1,2,3,4-tetrahydroisoquinoline CB 6-(benzyloxy)-1-[(E)-2-(3,4- 1.55 5.36 3.5dihydro-2H-1-benzopyran-6- yl)ethenyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline CC 6-(benzyloxy)-7-methoxy-1-[(E)-2- 1.18 5.444.6 (7-methyl-3,4-dihydro-2H-1- benzopyran-8-yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline CD 1-[(E)-2-[5-(4-azidobutoxy)-4- 0.088 1.63 18.5methoxy-2-methylphenyl]ethenyl]- 6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline CE 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.125 4.8738.9 (7-methyl-3,4-dihydro-2H-1- benzopyran-6-yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline CF 6-(benzyloxy)-1-[(E)-2-(3,4- 0.49 9.1 18.6dihydro-2H-1-benzopyran-8- yl)ethenyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline CG 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.14 4.834.3 (6-methyl-2,3-dihydro-1- benzofuran-5-yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline CH tert-butyl 2-[(E)-2-[6-(benzyloxy)-7- 0.583.48 6 methoxy-1,2,3,4- tetrahydroisoquinolin-1-yl]ethenyl]-1H-indole-1-carboxylate CI tert-butyl 3-[(E)-2-[6-(benzyloxy)-7- 0.234.98 21.7 methoxy-1,2,3,4- tetrahydroisoquinolin-1-yl]ethenyl]-1H-indole-1-carboxylate CJ 6-(benzyloxy)-1-[(E)-2-(1H-indol-3- 0.47 6.5513.9 yl)ethenyl]-7-methoxy-1,2,3,4- tetrahydroisoquinoline CK tert-butyl4-[(E)-2-[6-(benzyloxy)-7- 0.805 5.99 7.4 methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]ethenyl]- 1H-indole-1-carboxylate CL6-(benzyloxy)-1-[(E)-2-(1H-indol-4- 1.5 7.2 4.66yl)ethenyl]-7-methoxy-1,2,3,4- tetrahydroisoquinoline CM tert-butyl5-[(E)-2-[6-(benzyloxy)-7- 1.3 10 7.7 methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]ethenyl]- 1H-indole-1-carboxylate CNtert-butyl 7-[(E)-2-[6-(benzyloxy)-7- 1.83 19.6 11 methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]ethenyl]- 1H-indole-1-carboxylate CO3-[(E)-2-[6-(benzyloxy)-7-methoxy- 6 10 1.71,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]-2,6-difluorophenol CP6-(benzyloxy)-1-[(E)-2-(3- 3.07 20.6 6.7methanesulfonylphenyl)ethenyl]-7- methoxy-1,2,3,4-tetrahydroisoquinoline CQ 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.06 1.423.7 (7-methoxy-2,3-dihydro-1,4- benzodioxin-6-yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline CR 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.12 3.327.2 (6-methoxy-2H-1,3-benzodioxol-5- yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline CS tert-butyl 6-[(E)-2-[6-(benzyloxy)-7- 0.9126.15 6.7 methoxy-1,2,3,4- tetrahydroisoquinolin-1-yl]ethenyl]-1H-indole-1-carboxylate CT 2-[(E)-2-[6-(benzyloxy)-7-methoxy- 0.2 8.9 451,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]-4,5-dimethoxy-N,N-dimethylaniline CU 3-[(E)-2-[6-(benzyloxy)-7-methoxy- 1.4 19.9 141,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]-N,N-dimethylpyridin-2-amine CV ethyl 4-{5-[(E)-2-[6-(benzyloxy)-7- 0.1 2.7 20 methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]ethenyl]- 2-methoxyphenoxy}butanoate CWtert-butyl N-{2-[(E)-2-[6- 5.4 23.6 4.3 (benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]phenyl}carbamate CX2-[(E)-2-[6-(benzyloxy)-7-methoxy- 1.4 20.8 141,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]aniline CY6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.697 4 5.7 [4-methoxy-3-(trifluoromethyl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline CZ6-(benzyloxy)-7-methoxy-1-[(E)-2- 2.188 4 1.8 [4-methoxy-3-methyl-5-(trifluoromethyl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline DA6-(benzyloxy)-7-methoxy-1-[(E)-2- 2.34 10 4.3[2-(trifluoromethyl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline DB6-(benzyloxy)-7-methoxy-1-[(E)-2- 2.67 10 3.7[3-(trifluoromethyl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline DC2-[(E)-2-[6-(benzyloxy)-7-methoxy- 0.83 10 12.11,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]-N,N-dimethylaniline DD6-(benzyloxy)-7-methoxy-1-[(E)-2- 11.06 100 9(2-methoxypyrimidin-5-yl)ethenyl]- 1,2,3,4-tetrahydroisoquinoline DE6-(benzyloxy)-7-methoxy-1-[(E)-2- 1.44 10 6.9 [2-(2-methoxyethoxy)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline DF6-(benzyloxy)-1-[(E)-2-(2,2- 5.44 10 1.8 difluoro-2H-1,3-benzodioxol-5-yl)ethenyl]-7-methoxy-1,2,3,4- tetrahydroisoquinoline DG6-(benzyloxy)-7-methoxy-1-[(E)-2- 2.2 9 4.1 (2-methoxyphenyl)ethenyl]-1,2,3,4-tetrahydroisoquinoline DH 6-(benzyloxy)-7-methoxy-1-[(E)-2- 5.2617.8 3.4 [2-(morpholin-4-yl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline DI 6-(benzyloxy)-7-methoxy-1-[(E)-2-0.628 5.84 9.2 (6-methoxynaphthalen-2- yl)ethenyl]-1,2,3,4-tetrahydroisoquinoline DJ 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.393 5.8615 [4-(pyridin-3-yl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline DK6-(benzyloxy)-1-[(E)-2-[4-(1H- 0.107 9.13 85imidazol-1-yl)phenyl]ethenyl]-7- methoxy-1,2,3,4- tetrahydroisoquinolineDL 7-[(E)-2-[6-(benzyloxy)-7-methoxy- 0.0969 7 721,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]quinoline DM6-(benzyloxy)-7-methoxy-1-[(E)-2- 1.52 21.1 14[4-(2-methyl-1H-imidazol-1- yl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline DN 6-(benzyloxy)-7-methoxy-1-[(E)-2- 2.4 17.1 7.1[2-(3-methoxyphenyl)pyrimidin-5- yl]ethenyl]-1,2,3,4-tetrahydroisoquinoline DO 6-(benzyloxy)-1-[(E)-2-[4-(4- 0.496 3.61 7.3ethylpiperazin-1- yl)phenyl]ethenyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline DP 6-(benzyloxy)-7-methoxy-1-[(E)-2-0.015 1.3 92 {1-methyl-1H-pyrrolo[2,3-b]pyridin- 3-yl}ethenyl]-1,2,3,4-tetrahydroisoquinoline DQ 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.126 4.4 35[3-(pyridin-4-yl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline DR6-(benzyloxy)-7-methoxy-1-[(E)-2- 4.82 25.4 5.3(1,3-thiazol-4-yl)ethenyl]-1,2,3,4- tetrahydroisoquinoline DS6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.116 7.39 64[4-(pyrimidin-5-yl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline DT6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.157 7.39 47 [4-(1H-1,2,4-triazol-1-yl)phenyl]ethenyl]-1,2,3,4- tetrahydroisoquinoline DU1-[(E)-2-(1-benzothiophen-2- 10.1 16.3 1.6 yl)ethenyl]-6-(benzyloxy)-7-methoxy-1,2,3,4- tetrahydroisoquinoline DV6-(benzyloxy)-7-methoxy-1-[(E)-2- 29.5 21.8 0.74(1,3-thiazol-2-yl)ethenyl]-1,2,3,4- tetrahydroisoquinoline DW6-(benzyloxy)-7-methoxy-1-[(E)-2- 1.24 2.31 1.9 [4-(4-methylpiperazin-1-yl)phenyl]ethenyl]-1,2,3,4- tetrahydroisoquinoline DX6-(benzyloxy)-7-methoxy-1-[(E)-2- 4.2 5.38 1.3[2-(piperidin-1-yl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline DY6-(benzyloxy)-7-methoxy-1-[(E)-2- 5.51 21.6 3.9(4-methyl-1,3-thiazol-5-yl)ethenyl]- 1,2,3,4-tetrahydroisoquinoline DZ6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.65 5.8 8.9[4-(pyridin-2-yl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline EA6-(benzyloxy)-7-methoxy-1-[(E)-2- 2.1 4.8 2.3[4-(piperidin-1-yl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline EB6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.3 6 20 (6-methoxy-1-benzofuran-5-yl)ethenyl]-1,2,3,4- tetrahydroisoquinoline EC6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.93 7.5 8[3-(1,3-oxazol-2-yl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline ED6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.58 7.5 13[4-(1,3-oxazol-2-yl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline EEethyl 2-{4-[(E)-2-[6-(benzyloxy)-7- 0.99 5.9 2.8 methoxy-1,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]phenyl}-1,3-oxazole-4- carboxylateEF ethyl 2-{3-[(E)-2-[6-(benzyloxy)-7- 1 5.9 6 methoxy-1,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]phenyl}-1,3-oxazole-4- carboxylateEG 6-(benzyloxy)-1-[(E)-2-(2,3- 0.9 19.3 21.4 dihydro-1-benzofuran-6-yl)ethenyl]-7-methoxy-1,2,3,4- tetrahydroisoquinoline EH6-(benzyloxy)-1-[(E)-2-(2,4- 0.066 3.59 54.5 dimethoxy-5-methylphenyl)ethenyl]-7-methoxy- 1,2,3,4-tetrahydroisoquinoline EI6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.34 11.8 35.3 (4-methoxy-3-methylphenyl)ethenyl]-1,2,3,4- tetrahydroisoquinoline EJ6-(benzyloxy)-7-methoxy-1-[(E)-2- 2.98 10 3.3 (3-methoxyphenyl)ethenyl]-1,2,3,4-tetrahydroisoquinoline EK 6-(benzyloxy)-1-[(E)-2-(2,5- 0.38 3.69.5 dimethoxyphenyl)ethenyl]-7- methoxy-1,2,3,4- tetrahydroisoquinolineEL 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.15 3.25 21.7 (4-methoxy-2,3-dimethylphenyl)ethenyl]-1,2,3,4- tetrahydroisoquinoline EM6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.32 1.8 5.6[4-methoxy-3-(piperidin-1- ylmethyl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline EN 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.189 4.0321.3 {4-methoxy-3-[(2-methyl-1H- imidazol-1-yl)methyl]phenyl}ethenyl]-1,2,3,4- tetrahydroisoquinoline EO6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.504 1.94 3.8 {4-methoxy-3-[(2,2,2-trifluoroethoxy)methyl]phenyl}ethenyl]- 1,2,3,4-tetrahydroisoquinolineEP 6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.846 4 4.7 [4-methoxy-3-(methoxymethyl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline EQ4-[(E)-2-[6-(benzyloxy)-7-methoxy- 7.04 10 1.41,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]benzoic acid ER3-[(E)-2-[6-(benzyloxy)-7-methoxy- 10 10 11,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]benzoic acid ES2-[(E)-2-[6-(benzyloxy)-7-methoxy- 8.62 10 1.21,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]benzoic acid ET ethyl2-[(E)-2-[6-(benzyloxy)-7- 2.48 9.9 4 methoxy-1,2,3,4-tetrahydroisoquinolin-1- yl]ethenyl]benzoate EU6-(benzyloxy)-7-methoxy-1-[(E)-2- 0.24 5.1 21.3 [4-methoxy-3-(phenoxymethyl)phenyl]ethenyl]- 1,2,3,4-tetrahydroisoquinoline

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. It is to be understood that the presentinvention covers all combinations of aspects and/or embodiments, as wellas suitable, convenient and preferred groups described herein. Allpublications, patents, and patent applications cited herein are herebyincorporated by reference in their entirety for all purposes.

The invention is further illustrated by the Examples that follow. TheExamples are not intended to define or limit the scope of the invention.

What is claimed is:
 1. A compound which is:

in which R¹ is H or unsubstituted alkoxy or phenyl substituted alkoxy;R² is H or CF₃ or unsubstituted alkoxy or phenyl substituted alkoxy; R³is H or —C(O)OR⁴ or —C(O)R⁴ or —C(O)NR⁴R⁵ wherein R⁴ and R⁵ areindependently selected from unsubstituted alkyl, unsubstituted phenyl,or unsubstituted pyridinyl; A is substituted or unsubstituted phenyl, ora hydrate, solvate, or salt thereof.
 2. The compound of claim 1, whichis:

or a hydrate, solvate, or salt thereof.
 3. The compound of claim 1,which is:

or a hydrate, solvate, or salt thereof.
 4. The compound of claim 1,which is:

or a hydrate, solvate, or salt thereof.
 5. The compound of claim 1,which is:

or a hydrate, solvate, or salt thereof.
 6. A pharmaceutical formulationcomprising: a) a compound of a preceding claim, or a pharmaceuticallyacceptable salt thereof; and b) a pharmaceutically acceptable excipient.7. A method of inhibiting the replication of a virus in an animal,comprising: a) administering a compound or a pharmaceutical formulationof a preceding claim to the animal, wherein the animal is in need oftreatment thereof thereby inhibiting the replication of the virus in ananimal.
 8. The method of claim 7, wherein the virus is a member of theOrthoretroviridae family.
 9. The method of claim 7, wherein the virus isHIV.
 10. A method of treating a disease in an animal, comprising: a)administering a compound or a pharmaceutical formulation of a precedingclaim to the animal, wherein the animal is in need of treatment thereofthereby treating the disease in the animal.
 11. The method of claim 10,wherein the disease is AIDS.
 12. The method of any of claims 7-10,wherein the animal is a human.
 13. A method of treating an HIV infectionin a human, the method comprising administering to said human atherapeutically effective amount of a compound according to any ofclaims 1-5.